A Guide To…

Free Access

A Guide to IL-1 family cytokines in adjuvanticity

Natalia Muñoz-Wolf

Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland

Search for more papers by this author

Ed C. Lavelle,

Corresponding Author

Ed C. Lavelle

[email protected]

Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland

Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Advanced Materials and BioEngineering Research (AMBER), Trinity College Dublin, Ireland

Correspondence

E. C. Lavelle, Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland

Fax: +353 1 6772400

Tel: +353 1 8962488

E-mail: [email protected]

Search for more papers by this author

Natalia Muñoz-Wolf,

Natalia Muñoz-Wolf

Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland

Search for more papers by this author

Ed C. Lavelle,

Corresponding Author

Ed C. Lavelle

[email protected]

Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland

Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Advanced Materials and BioEngineering Research (AMBER), Trinity College Dublin, Ireland

Correspondence

E. C. Lavelle, Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, D02 PN40, Ireland

Fax: +353 1 6772400

Tel: +353 1 8962488

E-mail: [email protected]

Search for more papers by this author

First published: 15 April 2018

https://doi.org/10.1111/febs.14467

Citations: 38

Share a link

Email
Facebook
x
LinkedIn
Reddit
Wechat

Abstract

Growing awareness of the multiplicity of roles for the IL-1 family in immune regulation has prompted research exploring these cytokines in the context of vaccine-induced immunity. While tightly regulated, cytokines of the IL-1 family are normally released in response to cellular stress and in combination with other danger-/damage-associated molecular patterns (DAMPs), triggering potent local and systemic immune responses. In the context of infection or autoimmunity, engagement of IL-1 family receptors links robust innate responses to adaptive immunity. Clinical and experimental evidence has revealed that many vaccine adjuvants induce the release of one or multiple IL-1 family cytokines. The coordinated release of IL-1 family members in response to adjuvant-induced damage or cell death may be a determining factor in the transition from local inflammation to the induction of an adaptive response. Here, we analyse the effects of IL-1 family cytokines on innate and adaptive immunity with a particular emphasis on activation of antigen-presenting cells and induction of T cell-mediated immunity, and we address in detail the contribution of these cytokines to the modes of action of vaccine adjuvants including those currently approved for human use.

Abbreviations

APCs: antigen-presenting cells
cDCs: conventional dendritic cells
CMI: cell-mediated immunity
CTLs: cytotoxic T lymphocytes
DAMPs: danger-/damage associated molecular patterns
EAE: experimental autoimmune encephalomyelitis
GM-CSF: granulocyte-macrophage colony-stimulating factor
HMGB-1: high mobility group box 1
IFN: interferon
IFN-I: type I interferon
IL: interleukin
LCs: Langerhans cells
LPS: lipopolysaccharide
MAMPs: microbe-associated molecular patterns
MAPK: mitogen-activated protein kinase
MHC: major histocompatibility complex
MOA: mode of action
moDCs: monocyte-derived dendritic cells
NETs: neutrophil extracellular traps
NF‑κB: nuclear factor‑κB
NK: natural killer
PAD4: peptidylarginine deiminase 4
PBMCs: peripheral blood mononuclear cells
pDCs: plasmacytoid dendritic cells
RA: receptor antagonist
s.c.: subcutaneous
Tc: T cytotoxic
TCR: T-cell receptor
Th: T helper
TIR: Toll-IL-1-receptor
TLR: Toll-like receptor
WT: wild-type

Introduction

Vaccine adjuvants: current status and future challenges

Vaccination is one of the most successful and cost-effective medical interventions, having eradicated or nearly eradicated diseases such as smallpox, rubella and poliomyelitis. Traditional vaccines consist of attenuated or inactivated pathogens that provide antigen arrays combined with microbe-associated molecular patterns (MAMPs) that act as natural enhancers of immunity. Recombinant antigen production led to a shift towards well-defined subunit formulations which are less reactogenic but also less immunogenic [1]. Adjuvants became essential components of subunit formulations to enhance immunogenicity and boost subunit-vaccine efficacy.

Adjuvants influence the type, quality and breadth of the immune response. For 70 years, aluminium salts remained the only approved adjuvant for human use. Although the term alum strictly corresponds to potassium aluminum sulfate, the literature has adopted it to generally refer to most aluminium-containing adjuvants including aluminum hydroxide and aluminum phosphate. Hence in this review term alum generally refers to alum-containing adjuvants. Alum drives T helper 2 (Th2) and potent humoral responses sufficient to tackle pathogens with a stable antigen repertoire and their secreted toxins by promoting the generation of neutralising antibodies. However, protection against diseases such as tuberculosis, malaria, HIV, dengue and cancer also requires potent cell-mediated immunity (CMI) including Th1, Th17 and cytotoxic T lymphocytes (CTLs) [2, 3]. Since the 1990s, few new adjuvants have been licensed for human use. Among the newly licensed adjuvants, only AS01E has been shown to elicit protective Th1 cell-mediated immunity [4]. Three other adjuvant candidates in clinical development IC31, CAF01 and GLA-SE also induce strong T-cell responses in humans [3, 5-7]. Until now, adjuvants have been empirically developed, but as inadequate adjuvant selection may lead to vaccine failure even with a promising antigen, it is important that we understand the adjuvants’ modes of action (MOA) to select the most suitable candidate according to the type of response required [8]. Below we address the roles of IL-1 family cytokines in innate and adaptive immunity and their effects on activation of antigen-presenting cells and induction of T cell-mediated immunity. We present the evidence that IL-1 family members play key roles in adjuvant MOA and discuss how selective induction of IL-1 family cytokines by adjuvants could be harnessed to induce and direct cell-mediated immunity and improve vaccine efficacy.

An overview of the IL-1 family members: agonists, antagonists and receptors

The interleukin 1 (IL-1) cytokine family members are central mediators of immune responses and inflammation, regulating many processes in health and disease, with broad effects on immune and nonimmune cells [9]. IL-1 was the only identified member of the family until the cloning and expression of IL-1 DNA in 1984 revealed that it actually consisted of two proteins with overlapping effects: IL-1α and IL-1β [10]. Currently, the IL-1 family comprises 11 ligands including seven proinflammatory cytokines: IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ; three receptor antagonists (RA) which inhibit their biologic activities: IL-1RA (which blocks IL-1 receptor signalling) and IL-36RA and IL-38 (both antagonists for IL-36R). IL-37 is the only known anti-inflammatory cytokine of the IL-1 family [11, 12] (Table 1).

Table 1. IL-1 family members – Functions, receptors and processing

Common name	Alternative name	Subfamily	Receptor	Coreceptor	Antagonist/inhibitory receptor	Functions	Known secretion signal peptide	Proteolytic activation/inactivation	Protease/s	Released upon cell death	Expression
IL-1α	IL-1F1	IL-1	IL-1R1	IL-1RAcP	IL-1RA, IL-1R2	Proinflammatory	No	Active membrane-bound form and soluble precursor further activated by proteases [16]	Calpain, chymase, NE, GzmB [16]	Yes	Keratinocytes, thymus, hepatocytes, endothelial cells, fibroblasts, epithelial cells, monocytes, macrophages, DCs, B lymphocytes [12]
IL-1β	IL-1F2	IL-1	IL-1R1	IL-1RAcP	IL-1RA, IL-1R2	Proinflammatory	No	Produced as inactive pro-IL-1β, activated upon cleavage [16]	Casp-1 (inflammasome activation). Noncanonical casp-8; also NE, PR-3, CathG, chymase [16]	Yes	Primarily produced by monocytes, macrophages, and DCs (microglia). Low production by B cells and NK cells [12]
IL-18	IL-1F4	IL-18	IL-18Rα	IL-18Rβ	IL-18BP	Proinflammatory	No	Produced as inactive pro-IL-18, activated upon cleavage.	Casp-1 (inflammasome activation). GzmB, chymase.	Yes	Constitutively expressed in blood monocytes, intestinal epithelial cells (human). Also expressed in murine macrophages, DCs, endothelial cells, intestinal epithelial cells, and keratinocytes under steady state [155]
IL-33	IL-1F11	IL-1	ST2L (IL-1RL1)	IL-1RAcP	Soluble ST2 (sST2)	Proinflammatory	No	May be activated or inactivated by cleavage [16]	Activated by: CathG, chymase, NE. Inactivated by: Casp-3 and 7, poor substrate for casp-1 [156, 157]	Yes	Epithelial cells at barriers, i.e. skin, lung, intestine; adipocytes; endothelial cells; tumour cells [39]
IL-36α	IL-1F6	IL-36	IL-36R (IL-1Rrp2)	IL-1RAcP	IL-36RA	Proinflammatory	No	Cleavage at 9 amino acids N-terminal to a conserved A-X-Asp (K6) for optimal activity [134]	Unknown	Unknown	Monocytes, T/B cells, spleen, bone marrow, tonsils, lymph nodes, skin [134]
IL-36β	IL-1F8	IL-36	IL-36R (IL-1Rrp2)	IL-1RAcP	IL-36RA	Proinflammatory	No	Cleavage at 9 amino acids N-terminal to a conserved A-X-Asp (R5) for optimal activity [134]	Unknown	Unknown	Monocytes, T/B cells, bone marrow, tonsils, heart, lung, testis, colon, neurons, glial cells [134]
IL-36γ	IL-1F9	IL-36	IL-36R (IL-1Rrp2)	IL-1RAcP	IL-36RA	Proinflammatory	No	Cleavage at 9 amino acids N-terminal to a conserved A-X-Asp (S18) for optimal activity [134]	Unknown	Release noted in apoptotic keratinocytes [142]	Predominantly secreted by epithelial cells; also monocytes and THP1, macrophages and T cells; IL-36γ production induced in keratinocytes after TNF-α or PMA treatment [134, 158]
IL-1RA	IL-1F3	N/A	IL-1R1	–	N/A	Anti-inflammatory	Yes	No	N/A	Yes	Usually produced by the same cells that express IL-1α or IL-1β, i.e. monocytes, macrophages, DCS, neutrophils and epithelial cells [104]
IL-36RA	IL-1F5	IL-36	IL-36R (IL-1Rrp2)	Blocks IL-1RAcP recruitment	N/A	Anti-inflammatory	No	Removal of its N-terminal methionine [134]	Neutrophil elastase [159]	Unknown	Constitutively expressed in keratinocytes; present in monocytes, B cells, DCs, skin, brain, kidney, heart [134]
IL-37	IL-1F7	IL-18	IL-18Rα	SIGIRR (TIR8, IL-1R8) [160]	Unknown	Anti-inflammatory	No	Active precursor and cleaved forms. Casp-1 cleavage may promote nuclear translocation and anti-inflammatory activitya	Casp-1b, poor substrate for casp-4 [161]	No	Absent in mice. Expressed in human colonic plasma cells, tonsils, colonic lamina propria and stromal cells and skin cells [161], DCs, mononuclear cells and monocytes [162]
IL-38	IL-1F10	IL-36	IL-36R (IL-1Rrp2)	Blocks IL-1RAcP recruitment	Unknown	Anti-inflammatory	No	Unknown	Unknown	One study reporting release during apoptosis [163]	mRNA expressed in heart, placenta, fetal liver, skin, spleen, thymus and tonsil. Protein found in skin and proliferating B cells in the tonsils [164]

N/A, not applicable; IL, interleukin; RA, receptor antagonist; DCs, dendritic cells; NK, natural killer; NE, neutrophil elastase; GzmB, Granzyme B; Casp-, caspase; CathG, cathepsin G; PR-3, proteinase-3; PMA, phorbol-mirystate acetate; TNF-α, tumour necrosis factor alpha; mRNA, messenger ribonucleic acid.
^a Studies performed using recombinant human IL-37 in murine macrophages; results of this study must be carefully interpreted [165].
^b Cleavage of IL-37 by endogenous caspase-1 has not yet been definitely demonstrated as mutating the proposed caspase-1 cleavage site only marginally affects LPS-induced cleavage of IL-37. This may suggest that other proteases might be involved in processing of IL-37 [165].

Ten IL-1 family receptors (IL-1R) have been identified and named chronologically on their discovery as IL-1R1, IL-1R2, etc. Each cytokine binds to and signals through its cognate receptor, triggering recruitment of an accessory chain to form a heterotrimeric complex containing three immunoglobulin (Ig)-like regions. Receptor activation induces phosphorylation of Toll-IL-1-receptor (TIR) domains, activation of nuclear factor‑κB (NF‑κB) and mitogen-activated protein kinase (MAPK) (reviewed in [13, 14]).

Interestingly, the lack of a canonical secretion signal sequence is a common feature of most proinflammatory members of the IL-1 family cytokines and their release has been linked to cell death (Table 1) [15]. Many IL-1 family cytokines are produced as procytokines and require protease cleavage to gain full agonist properties (Table 1). IL-1β and IL-18, can be activated by multiprotein complexes known as inflammasomes which act as molecular platforms for procaspase-1 activation and processing of the procytokines into mature active forms (Fig. 1) [8]. Pro-IL-1β and pro-IL-18 can also be activated by neutrophil and mast cell proteases, granzymes and some apoptotic caspases (Table 1) [16]. IL-1α, IL-33 and IL-1RA can exert their effects without being cleaved, although processing by neutrophil proteases and granzymes from cytotoxic lymphocytes or natural killer (NK) cells greatly amplifies the proinflammatory activity of IL-1α and IL-33 [16].

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

The NLRP3 inflammasome is a key platform for activation of pro-IL-1β and pro-IL-18. NLRP3 expression and activation can be induced by a wide variety of agents including extracellular ATP, lysosomal rupture and Cathepsin B (CatB) release, mitochondrial stress and reactive oxygen species (ROS) production, or other DAMPs which are recognised by the leucine-rich repeats (LRR) in the NLRP3 sensor. Activation of NLRP3 triggers oligomerisation and recruitment of the adaptor ASC and procaspase-1 which interact via homotypic domains, leading to the autoproteolytic maturation of caspase-1, which in turn cleaves pro-1L-1β and pro-IL-18 promoting their secretion and unleashing their inflammatory potential. *In vitro*, activation of the NLRP3 inflammasome requires two signals: signal 1 typically involving pattern recognition receptor signalling which induces transcription of pro-IL-1β, and amplifies expression of some inflammasome components and pro-IL-18; and signal 2 (crystals, DAMPs, ionic or energetic imbalance, oxidative stress, etc.) which triggers inflammasome complex formation. Within the NLR protein family, in addition to NLRP3, NLRP1, NLRC4, NLRP6, NLRP7 and NLRP12 are inflammasome-forming receptors. Other receptor/sensor molecules such as PYHIN proteins including absent in melanoma 2 (AIM2) and interferon gamma-inducible protein 16 (IFI16) can also form inflammasomes. The inflammasomes that rely on caspase-1 for activation of pro-IL-1β and pro-IL-18 are known as “canonical inflammasomes”, while a noncanonical caspase-1-independent, caspase-11-dependent pathway has been described for NLRP3 which requires the protein gasdermin D and is triggered by intracellular lipopolysaccharide (LPS) [8, 143]. [Colour figure can be viewed at wileyonlinelibrary.com]

Receptor activation is tightly regulated by receptor antagonists (i.e. IL-1RA and IL-36RA), inhibitory receptors (i.e. IL-1R8, also known as SIGIRR or TIR8) and decoy receptors (IL-1R2 and IL-18-binding protein, IL-18BP) that prevent intracellular signalling and inhibit the cytokines’ actions to avoid pathologic inflammation [13, 15]. The biochemistry of IL-1 family cytokine processing is beyond the scope of this review and has been addressed elsewhere [9, 13, 17].

Modulation of innate and adaptive immunity by IL-1 family cytokines

Cellular immunity is key to protection against several pathogens and in immunity to cancer. T cells typically require three signals from antigen-presenting cells (APCs) for activation: 1) engagement of the T-cell receptor (TCR) by complexes of antigen and major histocompatibility complex (MHC) class I or II displayed on the APC surface; 2) costimulation by the APC via molecules including CD80, CD86 and CD40 which promote prosurvival signals in the T cell; and 3) secretion of polarising cytokines including many members of the IL-1 family, which trigger differentiation of naïve T cells into different T helper (Th) or T cytotoxic (Tc) subsets (Fig. 2) [18, 19]. Adjuvants can influence these three signals, shaping T-cell responses.

Influence of the IL-1 family of cytokines on antigen-presenting cells

IL-1α and IL-1β are potent activators of DC subsets including conventional (cDCs) and Langerhans cells (LCs) which are highly phagocytic cells populating the epidermis and the first line of defence against skin pathogens. LCs can differentiate into DCs that polarise naïve CD4⁺ T cells into Th2 [20], Th17 [21] or IL-22 secreting T cells [22] and prime and cross-prime CD8⁺ T cells [23]. IL-1α enhances maturation of human monocyte-derived DCs (moDCs), increasing their ability to stimulate allogeneic CD4⁺ T-cell responses and enhancing their secretion of interferon (IFN)-γ and IL-13 [24]. Similarly, IL-1β enhances CD40L-mediated activation of human DCs, augmenting their ability to drive IFN-γ secretion in T cells [25] and to produce IL-12 [26]. IL-1α activates LCs in vitro when combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) [27], whereas intradermal administration of IL-1β promotes LC migration into the lymph nodes [28], enhances MHC-II expression and naïve T-cell proliferation more efficiently than IL-1α [29]. It must be noted that since IL-1α and IL-1β use the same receptor and trigger identical signalling pathways, differences in the responses evoked by these cytokines are largely a consequence of the context in which they are released rather than a ligand-specific effect. It is also worth considering that while comparing IL-1α and IL-1β potency by injecting the recombinant proteins is a valid approach, these experiments may not mimic the in vitro or in vivo situations where IL-1α is mostly presented as a membrane-bound protein and do not always contemplate the effect of proteolytic activation of IL-1α.

IL-18 is expressed by human LCs and certain DC subsets in mice, displaying autocrine functions [30]. When injected intradermally, IL-18 induces migration of epidermal LCs into the draining lymph nodes, with an activity comparable to that of IL-1β and tumour necrosis factor (TNF)-α [31]. IL-18 stimulates migration of cDCs and plasmacytoid (pDCs) to the lymph nodes. Plasmacytoid DCs (pDCs) are specialised type I interferon (IFN-I)-producing cells and are potent mediators of antiviral immune responses. Besides, IL-18 synergises with IL-12 for Th1-polarisation of murine and human cells [30, 32, 33]. Although both IL-1β and IL-18 synergise with IL-12 for Th1 polarisation [34], it has been proposed that only IL-18 is required for IFN-γ production in vivo [35, 36].

IL-33 is associated with allergic inflammation and Th2 responses. DCs are sensitive to IL-33 stimulation as they express the membrane-bound IL-33 receptor ST2L (also known as IL-1RL1) and produce IL-33 which has autocrine [37, 38] and paracrine actions on immune and nonimmune cells (i.e. mast cells, basophils, innate lymphocytes, NK cells, eosinophils and macrophages [39]). In vitro, IL-33 induces IL-6 secretion and maturation of DCs which can stimulate Th2 responses [37, 40, 41]. In the airways, IL-33 promotes homing and activation of DCs, sensitising to allergic inflammation [40], whereas in the gut, IL-33 promotes tolerogenic DCs and expansion of regulatory T cells [42]. IL-33 also acts on macrophages, inducing M2 polarisation and upregulation of IL-13 in T cells, contributing to Th2 polarisation in vivo [43].

IL-36α, IL-36β and IL-36γ regulate skin inflammation in mice and humans [44-46]. Dermal macrophages, CD1a⁺ DCs and LCs express high levels of IL36R messenger RNA. Exposure to IL-36β and IL-1β stimulates similar cytokine secretion in LCs but IL-1β is a more potent activator of dermal macrophages than IL-36 [47], suggesting a nonredundant role for IL-1 family members in stimulation of skin APCs subsets. IL-36γ induces IL-18 and IL-12p70 secretion in moDCs which triggers IFN-γ production in T cells in vitro suggesting that IL-36γ can skew T-cell polarisation towards Th1/Tc1 responses. Human pDCs express IL-36R constitutively and at higher levels compared to myeloid DCs [48]. IL-36α and IL-36β can also induce maturation of human moDCs imprinting a Th1 polarising phenotype [49]. IL-36α can synergise with IFN-γ to induce upregulation of Toll-like receptor 4 (TLR4), CD14 and CD11c, facilitating phagocytosis of complement opsonised particles [49]. Murine bone marrow-derived DCs also express IL-36R and respond to IL-36α, IL-36β and IL-36γ by secreting IL-1β, IL-6, IL-12, TNF-α and upregulating maturation markers [50].

IL-37 is the only anti-inflammatory cytokine of the family and also modulates DC activation. IL-37 is absent in mice and its functions in humans have not been fully resolved. As IL-37 isoforms bind to IL-18Rα expressed in mice, a transgenic mouse model of human IL-37b isoform expression (IL-37tg) has been used to explore IL-37 function, showing that overexpression of IL-37 impairs splenic DC activation by lipopolysaccharide (LPS) [51]. IL-37tg mice produced less inflammatory cytokines and were protected against LPS challenge compared to wild-type (WT) mice. Silencing of IL-37 in human peripheral blood mononuclear cells (PBMCs) induced overproduction of IL-1β, IL-6 and TNF-α, whereas IL-37 impaired secretion of IL-1α, IL-1β, TNF-α and IL-8 in human monocytic and epithelial cell lines in the steady state and after stimulation with LPS [51]. Whether IL-37 can be induced by adjuvants remains unknown, but if excessively produced it could potentially have detrimental effects on vaccine priming of local innate responses.

Altogether these studies highlight the importance of IL-1 family members as regulators of APC-induced T-cell responses and potentially in vaccine adjuvant-induced CMI.

The IL-1 family cytokines as regulators of T-cell differentiation and function

The functions of the IL-1 family cytokines in T-cell biology go beyond lineage commitment of naïve T cells. Several members regulate activation and maintenance of differentiated effector and memory T cells. Below we discuss the main roles of IL-1 family cytokines in T-cell differentiation and lineage maintenance.

IL-1 was the first family member linked to T-cell differentiation, particularly Th17 cells. IL-1β synergises with cytokines including IL-6, IL-23, TGF-β and IL-21 to promote differentiation of naive CD4⁺ T cells into Th17 cells in mice and humans in vitro [52-54], and also in vivo in models of experimental autoimmune encephalomyelitis (EAE), vaccination or colitis [53, 55, 56]. IL-1 can directly act on naive and memory Th1, Th17 and Th2 cells regulating their expansion and survival upon antigen stimulation and enhancing B cell help as reflected by the higher antibody titres observed in mice immunised with ovalbumin and IL-1α or IL-β [57, 58]. It must be noted that some studies failed to demonstrate IL-1R1 expression on Th1 cells [59] despite others showing that Th1 cells respond to IL-1 [57]. Recent studies revealed an unexpected plasticity of Th17 cells which can differentiate into a “nonconventional” subset of Th1 cells upon prolonged exposure to IL-12. This Th17-derived Th1 subset expresses IL-1R1 and responds to IL-1 driving enhanced inflammatory responses in humans and mice [60].

IL-1β directly acts on antigen-specific CD8⁺ T cells to enhance their expansion, survival, migration and effector function, including expression of granzyme B and IFN-γ secretion [61, 62].

IL-18 seems to be more exclusively linked to the generation of Th1 cell responses. In vitro, IL-18 plus IL-12 promote Th1 differentiation [63]. However, most studies suggest that IL-18 has a more prominent role in CD4⁺ phenotype stabilisation rather than initial lineage commitment [64]. In vivo, IL-18 is required for induction of optimal CD8⁺ antiviral responses against influenza in an IL-12-independent manner [65]. Increasing evidence suggests that memory T cells carry out several antigen-independent effector functions and IL-18 has been implicated in the modulation of noncognate memory T-cell functions. During Salmonella infection in mice, DCs sense bacteria via the NLRC4 inflammasome, triggering IL-1β and IL-18 secretion. In this context, IL-18 (but not IL-1β) induces IFN-γ secretion from noncognate CD8⁺ memory T cells which are important for protection [66]. Similarly, monocyte-derived IL-18 plays a role in early activation of noncognate CD8⁺ T cells and protection against Listeria monocytogenes [67]. These results reveal an important role for IL-18 in reactivation of memory T cells even in the absence of cognate antigen that could be extremely relevant in vaccine-induced responses.

IL-33 directly influences almost all subsets of Th cells and certain Tc subsets [68]. IL-33 has been mainly linked to Th2 responses as it amplifies production of IL-4, IL-5 and IL-13 from polarised Th2 cells [41, 69] and also acts as a chemoattractant for Th2 cells [70]. While most evidence suggests that ST2L is absent in Th1 cells, it has been suggested that ST2L is transiently expressed in activated Th1 cells in a T-bet/STAT4-dependent fashion, and that ST2L deficiency in virus-specific Th1 cells impairs their function and expansion [71]. Tc1 lymphocytes express ST2L in a T-bet-dependent fashion and respond to IL-33 when combined with IL-12 in vitro by secreting IFN-γ [68]. In line with this, IL-33 contributes to antiviral defences during RNA and DNA viral infections in mice [72]. IL-33 proved to be an effective adjuvant in DNA vaccines encoding tuberculosis or human papillomavirus antigens and IL-33 isoforms. In this setting, coadministration of plasmids encoding IL-33 enhanced antigen-specific IFN-γ responses, polyfunctional CD4⁺ and CD8⁺ T cells and immunological memory [73, 74].

In models of colitis, IL-33 induced secretion of IL-9 in T cells [75] and was also shown to promote Treg expansion, Foxp3 and ST2L expression [76]. ST2L signalling in Tregs also ameliorates EAE by increasing Treg frequency which reduces IL-17 and IFN-γ production and pathology [42, 77, 78]. IL-33 also induces Treg infiltration and function in a model of skeletal muscle injury, promoting tissue repair [79]. Hence, although IL-33 can boost Tc1/Th1 responses, IL-33 can also boost Treg function, Th9 and Th2 responses highlighting that context-specific roles of IL-33 should be taken into account for rational adjuvant and vaccine design.

The IL-36 subfamily recently emerged as a regulator of T-cell function and differentiation as IL-36 family members were shown to stimulate secretion of IFN-γ, IL-4, and to a lesser extent IL-17 in cultured splenocytes and activated CD4⁺ T cells. Recombinant IL-36β acts as an adjuvant, stimulating Th1 responses in vivo [50]. IL-36R is predominantly expressed on naïve CD4⁺ T cells in mice which also constitutively express IL-36β. All three IL-36 cytokines stimulate proliferation and IL-2 secretion in naïve CD4⁺ T cells. When combined with IL-12 in vitro, IL-36β induces polarisation of naïve T cells into Th1 cells. Using a model of intravenous challenge with live Bacillus Calmette–Guerin (BCG), Vigne et al. showed that IL-36 cytokines are also required for optimal T-cell responses in vivo, as splenocytes from IL-36R KO mice had impaired secretion of IFN-γ, IL-6 and TNF-α upon ex vivo restimulation [80]. Nevertheless, impaired IL-36R signalling did not affect susceptibility to BCG infection [80, 81].

IL-36β or IL-36γ synergise with IL-12 or IL-2 to induce TCR-independent IFN-γ synthesis in CD8⁺ T cells [82], whereas IL-36γ can inhibit Tregs while promoting Th9 responses and intestinal inflammation [83]. Induction of IL-36 cytokines during vaccination could be a strategy for promoting Th1 responses.

IL-1 family cytokines and adjuvant modes of action

The diverse effects of IL-1 family members on APC function, T-cell differentiation and induction of cell-mediated immunity during infections or autoimmunity highlights the potential of exploiting these cytokines in the development of improved vaccines. Below we examine what is currently known about the involvement of IL-1 family members in the MOA of clinically approved adjuvants and other promising candidates for induction of CMI.

Adjuvants in licensed vaccines or in vaccines at advanced clinical stages

Alum-based adjuvants

Alum has been the most widely used adjuvant in human vaccines since the 1920s; nevertheless, its MOA remains incompletely understood. Alum drives a Th2-biased immune response accompanied by antibody responses, mainly of the IgG1 type in mice. Several mechanisms have been proposed to contribute to alum's MOA. An initial report by Li et al. put the IL-1 family at centre stage after showing that alum induced IL-1β and IL-18 secretion in a NLRP3-dependent fashion in vitro [84]. Soon, some suggested that NLRP3 and IL-1β were required for alum's adjuvanticity in vivo [85, 86]; however, despite several reports showing that alum induced NLRP3 activation and IL-1β secretion in vitro, the role for IL-1 or NLRP3 in alum's adjuvanticity in vivo has not been confirmed [87-90].

Alum injection induces the release of endogenous danger signals or alarmins from resident or recruited cells that die after encountering alum crystals. These alarmins, including uric acid, ATP, HMGB-1 (high mobility group box 1) protein, host DNA and intracellular cytokines including IL-1α and IL-33 have been proposed to mediate alum's adjuvanticity [8]. DNA released from dying cells was shown to be a major contributor to alum-induced adaptive immunity [91]; however, the cellular source of that DNA remained unidentified. Intraperitoneal alum injection induces neutrophil infiltration [92-94] in an IL-1-dependent and NLRP3-independent fashion, whereas IL-18 is not required for innate cell recruitment after intraperitoneal vaccination with alum [89]. As neutrophil extracellular traps (NETs) are a source of chromatin and other alarmins, it was hypothesised that these could contribute to alum's adjuvanticity [95]. A recent study by Stephen et al. [96] showed that mice deficient in peptidylarginine deiminase 4 (PAD4), the enzyme that catalyses histone hypercitrullination and chromatin decondensation during NET formation [97], had reduced CD4 T cells, B cells and IgG1 titres after alum injection, suggesting that NETs can contribute to the adjuvanticity of alum [96]. However, we found that despite the impaired neutrophil recruitment seen in IL-1R1 deficient mice, both humoral and CD8⁺ T-cell responses were fully intact after intraperitoneal alum injection [89]. In line with this, other studies have also reported intact humoral and/or cellular responses in mice depleted of neutrophils (using monoclonal antibodies) either after intraperitoneal [93] or intramuscular [98] vaccination with alum. A previous study by Munks et al. showed that several cell types form extracellular traps in response to alum injection which contribute to local formation of nodules composed by chromatin, histones and fibrin. Fibrin deficient mice with impaired nodule formation and reduced local accumulation of extracellular traps exhibited comparable cellular and adaptive responses to wild-types following injection of alum-containing vaccines [91]. Hence, despite the documented contribution of DNA to alum adjuvanticity [91], the role of local neutrophil recruitment and formation of extracellular traps remains controversial. As different vaccination routes were used in these studies, it is possible that the presence of NETs differentially impacts tissue-resident cells and cell recruitment, which may determine the type of local response elicited by the adjuvant.

It is worth noting that IL-1α, IL-1β and IL-18 induce IgG and IgE responses when administered intranasally with an antigen [99]. Moreover, instillation of alum in the lungs induces necrotic death of alveolar macrophages which results in IL-1α release and formation of inducible bronchus-associated lymphoid tissue in the lungs, Th2 responses and IgE production [100]. Thus, it is possible that the IL-1 family cytokines regulate alum-induced responses in a tissue-dependent manner which is dictated by the susceptibility of resident cells to alum-induced necrosis [95]. Alum-containing human vaccines are administered intramuscularly but many mechanistic studies have used alternative routes, hence more research will be required to assess this context-dependent contribution of IL-1 family cytokines to alum-induced humoral and cellular immunity.

A recent study explored the role of IL-33 in alum's adjuvant effect. Elevated IL-33 concentrations were detected locally after mice were injected with alum intraperitoneally. Lack of IL-33 or impaired IL-33 signalling reduced local cytokine and chemokine secretion (IL-5, IL-13, MCP-1, G-CSF) but IL-33 was not required for alum-induced antibody responses [101]. In conclusion, although IL-1 and IL-33 contribute to alum-induced innate responses, they seem to be dispensable for alum-induced IgG responses.

In line with the aforementioned studies, antigen-specific humoral responses were intact in MyD88 KO mice after intraperitoneal vaccination with alum-adsorbed antigens [102, 103]. As MyD88 mediates signal transduction upon engagement of the receptors for IL-1, IL-18, IL-33 and IL-36 (reviewed in [104]), it seems unlikely that these IL-1 family members play a prominent role as positive regulators of alum-induced antibody responses. The alum-containing adjuvant system AS04 incorporates the TLR4 agonist monophosphoryl lipid A (MPLA), a nontoxic derivative of LPS [105]. AS04 enhances antigen-specific T-cell responses compared to alum alone [106]. Intramuscular injection of this adjuvant transiently induces local NF-κB activation, cytokine production, antigen uptake and migration of DCs and monocytes to draining lymph nodes [106]. Although the specific role of IL-1 in the AS04 MOA has not yet been assessed, it is worth noting that contrary to LPS, MPLA poorly stimulates IL-1β secretion, does not induce NLRP3 expression and has been reported to suppresses activation NLRP3 [107]. Hence, it is unlikely that IL-1β plays an important role in AS04 MOA.

Squalene-containing oil-in-water emulsions – MF59, GLA-SE, AS03

MF59 was the first emulsion adjuvant licensed for human use in influenza vaccines (Table 2) after incomplete Freund's adjuvant (IFA) used in polio and influenza vaccines was withdrawn due to severe local reactogenicity [108]. MF59 is a well-tolerated squalene-based emulsion that enhances antibody production and Th1 responses in humans [109] and mixed Th1/Th2 responses in mice [110]. MF59 activates tissue-resident cells, i.e. macrophages and muscle cells, inducing cytokine and chemokine secretion and local innate infiltrates. MF59 triggers ATP release which acts as a danger signal and boosts adjuvanticity [110]. ATP can engage the purinergic P2X7 receptor and activate the NLRP3 inflammasome, inducing release of IL-1β and IL-18 [111, 112]. Nevertheless, NLRP3 is dispensable for MF59 adjuvanticity [113, 114]. It was suggested that the inflammasome adaptor protein ASC, which acts as a bridge between the inflammasome sensor (e.g. NLRP3, NLRC4, AIM2, among others) and caspase 1 (Fig. 1), was needed for MF59-induced antibody responses and cytokine secretion, implying that a different inflammasome could be required for MF59 adjuvanticity [114]. However, it must be noted that this result was not reproduced in a different Pycard^−/− (ASC KO) mouse strain [115] and may have been linked to a documented deficiency in ASC KO mice which affects Dock2, a central regulator of the cytoskeleton. Dock2 deficiency impairs lymphocyte migration, pDC function and antigen uptake [116]. Although more research is required to confirm these observations, the results suggest that inflammasome-derived IL-1 and IL-18 or ASC may not be required for MF59 adjuvanticity. Given the important role of purinergic receptor signalling in MF59 adjuvanticity, it is worth noting that exposure of bronchial epithelial cells to rhinoviruses or allergens induces an increase in extracellular ATP, activating purinergic receptor signalling which is linked to IL-33 release [117]. It would be interesting to investigate if MF59-triggered ATP release and P2X7 signalling in the skeletal muscle also results in the release of IL-33 and whether the release of IL-33 could play a role in MF59 adjuvanticity.

Table 2. Adjuvants licensed in human vaccines or at advanced clinical stages

Name	Type	Components	IL-1 family cytokines and adjuvant MOA	Vaccines	Administration route	Approval stage	Approval reference
Alum	Mineral salt	Aluminium oxyhydroxide or aluminium hydroxyphosphate	NLRP3-independent IL-1 and IL-33 promote innate recruitment. Not required for adjuvanticity [87-90, 101]	Various	Intramuscular	Licensed (worldwide)	Various
AS04	Mineral salt + TLR4 agonist	Alum-adsorbed MPLA	Not fully addressed; NLRP3-derived IL-1 seems dispensable [107]	Cervarix (HPV bivalent types 16 and 18) Fendrix (HBV)	Intramuscular	Licensed EU, USA. Withdrawn USA 2016. Europe	https://www.medscape.com/viewarticle/870853 [166]
MF59	Oil-in-water	Squalene, polysorbate 80, sorbitan trioleate, citrate buffer	NLRP3-derived IL-1 and IL-18 not required [113, 114]	Influenza (many: Fluad, Aflunov, Focetria, Celtura)	Intramuscular	Licensed (EU and or worldwide excluding USA)	[108]
AS03	Oil-in-water	Squalene, α-tocopherol, polysorbate 80, phosphate-buffered saline	ND	Influenza (many: Prepandrix, Pumarix, Pandemrix, Arepanrix)	Intramuscular	Licensed (EU and or worldwide excluding USA)	[108]
AS02	Oil-in-water	AS03 + MPLA and QS-21	NLRP3 shown to negatively regulate QS-21 adjuvanticity [122]. IL-1 family cytokine role in AS02 MOA remains unknown.	HBVAXPRO (HBV) FMP2.1/AS02A and RTS,S/AS02A (malaria) Mtb72F/AS02A (Tuberculosis) NefTat/gp120/AS02A (HIV)	Intramuscular	Phase III Phase II Phase II Phase I	NCT00291954/NCT00480116 NCT00460525/NCT00197054 NCT00146744 NCT00027365/NCT00117429
AF03	Oil-in-water	Squalene, polyoxyethylene cetyl-stearylether, sorbitan oleate, mannitol, phosphate-buffered saline	ND	Humenza (influenza)	Intramuscular	Approved by European Medicines Agency in 2010; withdrawn in 2011	[108]
GLA-SE	Oil-in-water	Glucopyranosyl lipid A in a stable squalene emulsion	NLRP3-independent secretion of IL-18 required for IFN-γ and CD8⁺ T cells [118]	ID93 + GLA-SE (tuberculosis) rSm14/GLA-SE (Schistosomiasis) LEP-F1 + GLA-SE (leprosy) PanBlok (Pandemic Influenza)	Intramuscular	Phase IIa (tuberculosis) Phase II (Schistosomiasis) Phase I (Leprosy) Phase I (influenza)	NCT02465216 NCT03041766 NCT03302897 NCT01612000
Montanide ISA-51	Water-in-oil	Squalene, mannide monooleate	ND	CIMAvax-EGF (lung cancer, therapeutic)	Intramuscular/subcutaneous	Licensed Cuba	[108]
AS01 adjuvants	Liposomes	Cholesterol, QS-21 and MPLA	ND	Mosquirix (malaria, RTS,S/AS01) and Shingrix (Hz/su, shingles)	Intramuscular	Mosquirix: approved by European Medicines Agency Shingrix: Phase III	http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_for_use_outside_EU/2015/10/WC500194576.pdf NCT02690207, NCT02735915
CAF01	Liposomes (cationic)	Two-component liposomal suspension with DDA and TDB	IL-1R signalling required for IL-17 and IFN-γ production but not for antibodies [126]	Ag85B-ESAT-6:CAF01	Intramuscular	Phase I	NCT00922363
IC31	Cationic particles	11-mer antibacterial peptide KLKL(5)KLK and synthetic immunostimulatory oligodeoxynucleotide	ND	H1/H56: IC31 SSI, Valneva, Aeras and H4:IC31 Sanofi Pasteur, SSI, Aeras (both tuberculosis)	Intramuscular	Phase IIa	http://www.aeras.org/img/uploads/attachments/Tait_Stakeholder_102016_-_2.pdf
ISCOMATRIX	Self-assembled nanoparticles	Quillaja saponins, cholesterol and phospholipids at a molar ratio ~ 1 : 1 : 1	NLRP3, NLRC4-independent IL-18 required for IFN-γ and IgG2c [124]	NY-ESO-1:ISCOMATRIX (melanoma) V950:ISCOMATRIX (Alzheimer) Octavalent HPV:ISCOMATRIX V180:ISCOMATRIX (dengue)	Intramuscular	Phase II Phase I Phase I Phase I	NCT00518206 NCT00464334 NCT00851643 NCT01477580

MPLA, 3-O-desacyl-4ʹ-monophosphoryl lipid A; TLR, Toll-like receptor; AS, adjuvant system; AF, adjuvant formulation; EGF, epidermal growth factor; QS, Quillaja saponaria, HPV, human papilloma virus; TDB, α,α’-trehalose dibehenate; DDA, N,N’-dimethyl-N,N’-dioctadecylammonium bromide; HCS, Hepatitis C virus; HBV, Hepatitis B virus; ND, not determined.

The adjuvant GLA-SE consists of the synthetic TLR4 agonist glucopyranosyl lipid A in a stable squalene-in-water emulsion [118]. GLA-SE is in Phase I clinical trials for vaccines for influenza, leishmaniasis, schistosomiasis, malaria and tuberculosis, showing robust enhancement of Th1 and balanced IgG1/IgG2 responses in humans [108]. Induction of Th1 responses by GLA-SE requires MyD88, TRIF, T-bet and IL-12 signalling in addition to IFN-I supporting IFN-γ secretion by memory CD8⁺ T cells and NK cells [119, 120]. Regarding involvement of IL-1 family cytokines in its MOA, the injection of GLA-SE into the footpad of mice induced IL-18 in the local draining lymph nodes, stimulating noncognate CD8⁺ T cells with a memory phenotype which secreted IFN-γ and enhanced the activation marker CD69 [118]. The same study showed that GLA-SE also promotes migration of IFN-γ⁺ neutrophils carrying the vaccine antigen into the lymph nodes of mice where they colocalise with T cells. NLRP3 is dispensable for GLA-SE adjuvanticity, and while IL-18R1 and caspase1/11 are not required for cell recruitment, they regulate the expression of IFN-γ [118]. These results underscore the role of IL-18 in the GLA-SE MOA and highlight the contribution of neutrophils in IL-18-induced IFN-γ production after vaccination with antigen and GLA-SE. It remains to be determined if neutrophil-derived IFN-γ is required for GLA-SE adjuvant effect and how inflammasomes, other than NLRP3, contribute to IL-18 activation and GLA-SE adjuvanticity.

Regarding the role of IL-1 family cytokines in the adjuvanticity of AS03, very little is known. AS03 injection induces early and transient expression of inflammatory cytokines including IL-1β in the muscle [121] but the role of IL-1β in the adjuvanticity of AS03 has not yet been explored.

QuilA and QS-21-containing adjuvants: AS02, AS01, ISCOM/ISCOMATRIX

Saponins, derived from the soapbark tree Quillaja saponaria are amphipathic triterpene glycosides with intrinsic adjuvanticity. QuilA®, a mixture of Quillaja derived saponins has been used in veterinary vaccines and induces potent humoral and cellular responses. Saponins can be quite toxic as they are haemolytic. QS-21, a fraction of QuilA® exhibits robust adjuvanticity and low toxicity when formulated in cholesterol-containing liposomes [122]. Saponin-containing adjuvants including AS01 (cholesterol-containing liposomes, QS-21 and MPLA) and AS02 (Squalene oil-in-water emulsion AS03 plus MPLA and QS-21) have been licensed in human vaccines or are at advanced clinical development stages (see Table 2). The ISCOMATRIX™/Matrix-M™ adjuvants are self-assembling 40 nm particles containing QuilA, cholesterol and phospholipids in phase I and phase II trials (Table 2).

QuilA induces IL-1β release in human PBMCs and murine macrophages (requiring NLRP3 in the latter) [86]. The adjuvant QS-21 promotes antigen-specific antibody responses, Th1 and cytotoxic CD8⁺ T cells in primates and mice; however, CD8⁺ responses are normally weak in humans vaccinated with the QS-21 containing adjuvant AS01 and a subunit antigens [123]. In mice, QS-21 stimulates innate immunity by enhancing NK cell function and inflammatory cytokine release and induces NLRP3-dependent release of IL-1β and IL-18 in murine DCs and macrophages in vitro [122]. Surprisingly, NLRP3 was reported to negatively regulate QS-21-induced humoral and cellular responses in vivo as NLRP3-deficient mice immunised intramuscularly with HIV-1 gp120 and QS-21 had significantly higher Th1 and Th2 responses and increased IgG1 and IgG2c titres compared to WT controls [122]. The molecular basis of this finding remains unknown and the role of IL-1 in QS-21 adjuvanticity in vivo remains to be assessed.

The saponin-containing adjuvant ISCOMATRIX™ (IMX) induces humoral responses and shows an unparalleled ability to induce Ag-specific CD8⁺ T cells in humans compared to other saponin-containing adjuvants such as AS01 or AS02 [124]. In mice, IMX promotes early activation of NK cells and IFN-γ production and induces NLRP3-dependent IL-1β and IL-18 secretion in DCs in vitro. However, only IL-18 is required in vivo for IMX-induced IFN-γ production, NK cell activation, priming of antigen-specific CD8⁺ T cells and antibody class switching to IgG2c, which is independent of NLRP3 or NLRC4. Interestingly, ASC-deficient mice had a partial impairment in NK cell activation and IFN-γ production [124]. Based on these results, the authors concluded that inflammasome-dependent and independent sources of IL-18 may contribute to IMX adjuvant effects, but as mentioned before, this conclusion must be interpreted with care as ASC KO mice may also have a defect in Dock2. In any case, the requirement of IL-18 for IMX adjuvanticity seems clear although inflammasomes may be dispensable for its activation. IMX induces cell death [124] which may contribute to release of intracellular pro-IL-18. As pro-IL-18 can be activated by proteases such as granzyme B produced by activated NK cells, inflammasomes may not be essential for its activation.

Overall, the current evidence suggests that Quillaja-derived saponins presented in the form of small nanoparticles can induce release of IL-18 which is essential for the adjuvant activity of ISCOMATRIX adjuvants. Regarding the role of the licensed human adjuvants AS01 and AS02 that contain QS-21, the role of NLRP3, IL-1 and other IL-1 family cytokines remains to be determined.

Cationic particulates: CAF01 and IC31

The cationic adjuvants CAF01 (Statens Serum Institut) and IC31 (Valneva Technologies) are two promising candidates for tuberculosis vaccines in clinical phase I and phase IIa trials, respectively. Both consist of cationic particulates. CAF01 is composed of cationic liposomes containing N,N’-dimethyl-N,N’-dioctadecylammonium bromide (DDB) and the immunostimulatory α,α’-trehalose dibehenate (TDB), a synthetic analogue of the mycobacterial cord factor trehalose-6,6-dimycolate (TDM) a Mincle agonist [3, 125]. IC31 contains an immunostimulatory oligodeoxynucleotide ODN1a (a TLR9 agonist) and an 11-mer antibacterial peptide (KLK) which spontaneously forms particles when combined with antigens [125]. Both adjuvants are potent stimulators of T-cell responses, with CAF01 triggering Th1/Th17 responses, while IC31 favours Th1 responses, although generally these two adjuvants induce lower antibody titres when compared with MF59 or alum in mice immunised subcutaneously [125].

The role of the IL-1 family cytokines in the MOA of CAF01 and IC31 has not been explored in detail. Indeed to date, there are no reports assessing the involvement of IL-1 family cytokines in IC31 adjuvanticity and only one report has evaluated the contribution of one the components of CAF01, TDB on the induction of some IL-1 family members [126]. The C-type lectin receptor Mincle was previously identified as the receptor for TDM and the synthetic analogue TDB included in CAF01, which triggers FcRc-Syk-Card9 signalling, APC activation and adjuvanticity [127]. Although MyD88 was not required for stimulation of APCs by CAF01 in vitro, MyD88 KO mice showed impaired antigen-specific IFN-γ and IL-17 production as well as lower IgG2a titres after vaccination with CAF01 and the tuberculosis antigen H1. The MyD88 requirement was not linked to TLR2, TLR3, TLR4, TLR9 or TLR7 signalling as TLR2/3/4/7 quadruple knockouts and TLR9 KO responded normally to immunisation with TDB. As TDB induces the expression and secretion of IL-1β in macrophages in vitro and MyD88 is required for IL-1, IL-18 and IL-33 signalling, the authors analysed the contribution of these IL-1 family cytokines in adjuvanticity of CAF01. Interestingly, IL-1R1-signalling deficiency or administration of an IL-1 receptor antagonist abrogated IL-17 and IFN-γ production in vaccinated mice but did not affect antibody production. IL-18 and ST2 were not required for adjuvant activity although less inflammation was observed at the injection site in IL-18 KO mice injected with CAF01 compared to WT controls [126]. The defect seen in MyD88-deficient mice was probably linked to impaired IL-1R signalling, which is necessary for CAF01 adjuvanticity.

IL-1 family cytokines and chitosan

The cationic polysaccharide chitosan derived from partial deacetylation of chitin (a major component of crustacean and arthropod exoskeletons) has been approved for human use in cosmetics, food supplements, bandages and other biomedical applications and holds great adjuvant potential. We and others showed that chitosan induces inflammasome-dependent IL-1β secretion in DCs and macrophages in vitro [128-130]. When combined with the TLR9 agonist CpG, chitosan induced potent NLRP3-dependent Th1/Th17 responses in vivo. In addition, NLRP3- and IL-1R1-deficient mice show reduced antigen-specific IgG2b and IgG2c titres following vaccination with chitosan-CpG [129]. We have recently found that chitosan induces mitochondrial stress leading to release of DNA into the cytosol, triggering the DNA sensing cGAS-STING pathway. This leads to IFN-I secretion and DC maturation, stimulating Th1 responses, IFN-γ production, antibody secretion and class switching [130]. Although IFN-I have been shown to suppress NLRP3 inflammasome and IL-1β activation by caspase-1 via a mechanism involving STAT-1 [131], we showed that NLRP3 is required for chitosan-induced Th1 response as this response was abrogated in NLRP3 KO mice. It is worth noting that antibody responses were intact in NLRP3 KO mice [130]. This highlights the need to evaluate both the humoral and cellular responses when determining the MOA and signalling pathways involved in the adjuvanticity of different formulations.

Conclusion

Growing evidence implicates members of the IL-1 cytokine family in the differentiation and function of Th1, Th17 and cytotoxic T cell responses, yet this effect seems largely context-dependent. For example, while IL-1 enhances the survival, expansion and effector function of antigen-specific CD8⁺ T cells in vivo during L. monocytogenes or vaccinia virus infection, or in a tumour model [61, 62], IL-1 can promote Th2 responses when administered intranasally [132]. Similarly, IL-18 can support both Th1 or Th2 responses depending on the availability of IL-12 [133]. IL-33 has been mainly linked to amplification of Th2 responses [41, 69] particularly in the airways [40], but in the gut, IL-33 promotes regulatory T cells [42], whereas when IL-33 is combined with IL-12, Tc1 lymphocytes expressing ST2L respond by secreting IFN-γ [68]. IL-33 also contributes to antiviral immunity in vivo [72] and enhances antigen-specific IFN-γ responses, polyfunctional CD4⁺ and CD8⁺ T cells and immunological memory when used as an adjuvant in DNA vaccines [73, 74]. The IL-36 subfamily has also emerged as a prominent driver of Th1 responses and IFN-γ being most prominent in the skin [134]. In this regard, it is important to note that the injection route plays a critical role in determining which IL-1 family members are being released in response to an adjuvant as the expression patterns of IL-1 family members vary depending the tissue and recruited cell types. At the same time, the expression pattern of cytokine receptors will influence the downstream response. Furthermore, as most IL-1 family members are subject to processing by proteases [16], the proteases released by resident or recruited cells at the injection site may also play a key role in determining the activation or inactivation of different IL-1 family cytokines [97].

Clinical and experimental evidence indicates that most adjuvants cause local irritation and some degree of cytotoxicity stimulating DAMP release which may act as endogenous immune enhancers for adjacent viable cells at the injection site (Fig. 3). The DAMPs released in response to adjuvants are structurally diverse, ranging from extracellular ATP and uric acid to chromatin or mitochondrial DNA [91, 109, 110, 122, 130]. While these molecules may be immunostimulatory in certain contexts, research suggests that the release of preformed DAMPs per se may not always be sufficient to elicit an effective immune response. This was illustrated by studies where cells undergoing accidental necrosis after freeze-thawing cycles or boiling were unable to activate DCs in vitro or to elicit protective immunity against tumours in vivo [117, 135, 136]. In contrast, preactivation of cells prior to induction of cell death by γ-irradiation resulted in activation of DCs and promoted T-cell proliferation in vitro, an effect not seen when the same cells were killed without prior activation [137]. This implies that the expression and/or activation of canonical DAMPs must be initiated and precisely timed, before cell death is induced to trigger effective adaptive responses. As elegantly presented in a recent review [97], the IL-1 family members have all the characteristics of canonical DAMPs which can be induced when danger or damage is detected and released by dying cells. IL-1 family cytokines are tightly regulated, signal though very specific receptors that share signalling components with innate receptors (namely TLRs), and like TLRs, activation of the IL-1 family receptors links robust innate responses to adaptive immunity in the context of infection and autoimmunity [97]. Therefore, the coordinated release of IL-1 family members with an array of preformed DAMPs in response to adjuvant-induced cell death may be a key factor acting as a tipping-point in the transition from inflammation to the induction of an adaptive response (Fig. 3).

Adjuvants induce cell death by different mechanisms: alum activates lysosomal-mediated necrosis in macrophages [138, 139] and netosis in neutrophils and mast cells [93, 96]; ISCOMATRIX also triggers lysosomal destabilisation and necrosis in macrophages [124], whereas MF59 elicits apoptotic-like death in macrophages [109] and saponins and surfactant-containing adjuvants induce caspase-independent cytolysis [122, 140, 141]. As most IL-1 family cytokines lack conventional secretion signals, their release is largely linked to some form of cell death (Table 1) [15]. The type of cell death differentially regulates the release and activity of IL-1 family cytokines and while necrotic cell death promotes the release of IL-33 [39], activation of the proapoptotic caspases 3 and 7 inactivates IL-33 [16]. On the other hand, IL-36γ released from keratinocytes requires a cell death mechanism that involves activation of caspase-1 which induces IL36G gene expression and caspases 3/7 for IL-36γ secretion [142]. While inflammasome and caspase 1/11-mediated pyroptosis is possibly the best characterised mechanism linking cell death with maturation and release of IL-1β and IL-18 [143], the inflammasome does not seem to play a major role during adjuvant-induced release of IL-1 or IL-18 in vivo suggesting that other mechanisms may be more relevant. Recently, necroptosis and components of the necroptosome have been shown to regulate IL-1α and IL-1β secretion in vitro and during inflammatory autoimmune conditions [144, 145]; however, it remains to be determined if adjuvants can induce necroptosis and if this may impact adjuvanticity. Hence, the contribution of the IL-1 family members to adjuvanticity may be directly linked to the susceptibility of resident cells to adjuvant-induced cell death and studying how cell death triggered by adjuvants regulates IL-1 family members in vivo may contribute to unveiling the adjuvants MOA.

Most vaccines are administered into the skeletal muscle, a “nonclassical” immune-privileged tissue that despite not being separated by the typical anatomical barriers encountered in sites such as the brain and the eye, presents few immune cells under homeostasis and supports immunomodulatory responses by recruiting alternatively activated macrophages and Tregs in response to sterile inflammation, which favour regeneration and limit autoimmunity [137]. However, many studies addressing the adjuvants MOA utilise other immunisation routes that may not be representative of the real environment the adjuvant will encounter when injected in patients.

It is interesting to note that IL-1 family cytokines act as strong adjuvants when administered mucosally. For example, intranasal administration of IL-18 with influenza hemagglutinin (HA) induced the secretion of Th1 and Th2 cytokines, increased serum IgG levels and mucosal IgA [146], while intranasal immunisation of mice with IL-1α and a HIV antigen induced CTL responses and antigen-specific IFN-γ secretion [147]. Therefore, the role of IL-1 family cytokines in the MOA of mucosal adjuvants deserves more attention, as the induction of these cytokines could be the key to development of much needed mucosal adjuvants.

The intricate immune mechanisms triggered by administration of an adjuvant and the complex biology of the IL-1 family cytokines highlight the importance of studying adjuvant-induced responses in an appropriate context, one that can more closely reflect the route of vaccination in a clinical setting.

Acknowledgments

We sincerely thank Dr Michael Carty for his critical reading of the review and valuable discussions. This work has been supported by the Irish Research Council GOIPD-2017-1257 (NMW) and Science Foundation Ireland Investigator Award 12/1A/1421 (ECL). We apologise to the authors whose work could not be cited due to space limitations.

References

1Greenwood B (2014) The contribution of vaccination to global health: past, present and future. Philos Trans R Soc Lond B Biol Sci 369, 20130433.
10.1098/rstb.2013.0433
PubMedWeb of Science®Google Scholar
2Rappuoli R & Aderem A (2011) A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature 473, 463–469.
10.1038/nature10124
CASPubMedWeb of Science®Google Scholar
3Christensen D (2016) Vaccine adjuvants: why and how. Hum Vaccin Immunother 12, 2709–2711.
10.1080/21645515.2016.1219003
PubMedWeb of Science®Google Scholar
4Penn-Nicholson A, Geldenhuys H, Burny W, van der Most R, Day CL, Jongert E, Moris P, Hatherill M, Ofori-Anyinam O, Hanekom W et al. (2015) Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting. Vaccine 33, 4025–4034.
10.1016/j.vaccine.2015.05.088
CASPubMedWeb of Science®Google Scholar
5Kool M, Soullie T, van Nimwegen M, Willart MA, Muskens F, Jung S, Hoogsteden HC, Hammad H & Lambrecht BN (2008) Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med 205, 869–882.
10.1084/jem.20071087
CASPubMedWeb of Science®Google Scholar
6van Dissel JT, Arend SM, Prins C, Bang P, Tingskov PN, Lingnau K, Nouta J, Klein MR, Rosenkrands I, Ottenhoff TH et al. (2010) Ag85B-ESAT-6 adjuvanted with IC31 promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in naive human volunteers. Vaccine 28, 3571–3581.
10.1016/j.vaccine.2010.02.094
CASPubMedWeb of Science®Google Scholar
7van Dissel JT, Joosten SA, Hoff ST, Soonawala D, Prins C, Hokey DA, O'Dee DM, Graves A, Thierry-Carstensen B, Andreasen LV et al. (2014) A novel liposomal adjuvant system, CAF01, promotes long-lived Mycobacterium tuberculosis-specific T-cell responses in human. Vaccine 32, 7098–7107.
10.1016/j.vaccine.2014.10.036
CASPubMedWeb of Science®Google Scholar
8Muñoz-Wolf N, McCluskey S & Lavelle EC (2016) The role of inflammasomes in adjuvant-driven humoral and cellular immune responses. In Immunopotentiators in Modern Vaccines ( VEJC Schijns & DT O'Hagan, eds), pp. 23–42. Elsevier/Academic Press, Amsterdam.
Google Scholar
9Garlanda C, Dinarello CA & Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39, 1003–1018.
10.1016/j.immuni.2013.11.010
CASPubMedWeb of Science®Google Scholar
10Lomedico PT, Gubler U, Hellmann CP, Dukovich M, Giri JG, Pan YC, Collier K, Semionow R, Chua AO & Mizel SB (1984) Cloning and expression of murine interleukin-1 cDNA in Escherichia coli. Nature 312, 458–462.
10.1038/312458a0
CASPubMedWeb of Science®Google Scholar
11Sims JE, Nicklin MJ, Bazan JF, Barton JL, Busfield SJ, Ford JE, Kastelein RA, Kumar S, Lin H, Mulero JJ et al. (2001) A new nomenclature for IL-1-family genes. Trends Immunol 22, 536–537.
10.1016/S1471-4906(01)02040-3
CASPubMedWeb of Science®Google Scholar
12Netea MG, van de Veerdonk FL, van der Meer JW, Dinarello CA & Joosten LA (2015) Inflammasome-independent regulation of IL-1-family cytokines. Annu Rev Immunol 33, 49–77.
10.1146/annurev-immunol-032414-112306
CASPubMedWeb of Science®Google Scholar
13Boraschi D & Tagliabue A (2013) The interleukin-1 receptor family. Semin Immunol 25, 394–407.
10.1016/j.smim.2013.10.023
CASPubMedWeb of Science®Google Scholar
14O'Neill LA (2008) The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 226, 10–18.
10.1111/j.1600-065X.2008.00701.x
CASPubMedWeb of Science®Google Scholar
15Sims JE & Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10, 89–102.
10.1038/nri2691
CASPubMedWeb of Science®Google Scholar
16Afonina IS, Muller C, Martin SJ & Beyaert R (2015) Proteolytic processing of interleukin-1 family cytokines: variations on a common theme. Immunity 42, 991–1004.
10.1016/j.immuni.2015.06.003
CASPubMedWeb of Science®Google Scholar
17Garlanda C, Riva F, Bonavita E, Gentile S & Mantovani A (2013) Decoys and regulatory “receptors” of the IL-1/Toll-Like receptor superfamily. Front Immunol 4, 180.
10.3389/fimmu.2013.00180
PubMedWeb of Science®Google Scholar
18Walsh KP & Mills KH (2013) Dendritic cells and other innate determinants of T helper cell polarisation. Trends Immunol 34, 521–530.
10.1016/j.it.2013.07.006
CASPubMedWeb of Science®Google Scholar
19Kapsenberg ML (2003) Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol 3, 984–993.
10.1038/nri1246
CASPubMedWeb of Science®Google Scholar
20Furio L, Briotet I, Journeaux A, Billard H & Peguet-Navarro J (2010) Human langerhans cells are more efficient than CD14(-)CD1c(+) dermal dendritic cells at priming naive CD4(+) T cells. J Invest Dermatol 130, 1345–1354.
10.1038/jid.2009.424
CASPubMedWeb of Science®Google Scholar
21Mathers AR, Janelsins BM, Rubin JP, Tkacheva OA, Shufesky WJ, Watkins SC, Morelli AE & Larregina AT (2009) Differential capability of human cutaneous dendritic cell subsets to initiate Th17 responses. J Immunol 182, 921–933.
10.4049/jimmunol.182.2.921
CASPubMedWeb of Science®Google Scholar
22Fujita H, Nograles KE, Kikuchi T, Gonzalez J, Carucci JA & Krueger JG (2009) Human Langerhans cells induce distinct IL-22-producing CD4 + T cells lacking IL-17 production. Proc Natl Acad Sci USA 106, 21795–21800.
10.1073/pnas.0911472106
CASPubMedWeb of Science®Google Scholar
23Klechevsky E, Morita R, Liu M, Cao Y, Coquery S, Thompson-Snipes L, Briere F, Chaussabel D, Zurawski G, Palucka AK et al. (2008) Functional specializations of human epidermal Langerhans cells and CD14 + dermal dendritic cells. Immunity 29, 497–510.
10.1016/j.immuni.2008.07.013
CASPubMedWeb of Science®Google Scholar
24Matjeka T, Summerfield V, Noursadeghi M & Chain BM (2012) Chemical toxicity to keratinocytes triggers dendritic cell activation via an IL-1alpha path. J Allergy Clin Immunol 129, 247–250. e241-243.
10.1016/j.jaci.2011.08.018
CASPubMedWeb of Science®Google Scholar
25Luft T, Jefford M, Luetjens P, Hochrein H, Masterman KA, Maliszewski C, Shortman K, Cebon J & Maraskovsky E (2002) IL-1 beta enhances CD40 ligand-mediated cytokine secretion by human dendritic cells (DC): a mechanism for T cell-independent DC activation. J Immunol 168, 713–722.
10.4049/jimmunol.168.2.713
CASPubMedWeb of Science®Google Scholar
26Wesa AK & Galy A (2001) IL-1 beta induces dendritic cells to produce IL-12. Int Immunol 13, 1053–1061.
10.1093/intimm/13.8.1053
CASPubMedWeb of Science®Google Scholar
27Heufler C, Koch F & Schuler G (1988) Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells. J Exp Med 167, 700–705.
10.1084/jem.167.2.700
CASPubMedWeb of Science®Google Scholar
28Cumberbatch M, Dearman RJ & Kimber I (1997) Interleukin 1 beta and the stimulation of Langerhans cell migration: comparisons with tumour necrosis factor alpha. Arch Dermatol Res 289, 277–284.
10.1007/s004030050193
CASPubMedWeb of Science®Google Scholar
29Enk AH, Angeloni VL, Udey MC & Katz SI (1993) An essential role for Langerhans cell-derived IL-1 beta in the initiation of primary immune responses in skin. J Immunol 150, 3698–3704.
10.4049/jimmunol.150.9.3698
CASPubMedWeb of Science®Google Scholar
30Stoll S, Jonuleit H, Schmitt E, Muller G, Yamauchi H, Kurimoto M, Knop J & Enk AH (1998) Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development. Eur J Immunol 28, 3231–3239.
10.1002/(SICI)1521-4141(199810)28:10<3231::AID-IMMU3231>3.0.CO;2-Q
CASPubMedWeb of Science®Google Scholar
31Cumberbatch M, Dearman RJ, Antonopoulos C, Groves RW & Kimber I (2001) Interleukin (IL)-18 induces Langerhans cell migration by a tumour necrosis factor-alpha- and IL-1beta-dependent mechanism. Immunology 102, 323–330.
10.1046/j.1365-2567.2001.01187.x
CASPubMedWeb of Science®Google Scholar
32Stober D, Schirmbeck R & Reimann J (2001) IL-12/IL-18-dependent IFN-gamma release by murine dendritic cells. J Immunol 167, 957–965.
10.4049/jimmunol.167.2.957
CASPubMedWeb of Science®Google Scholar
33Gutzmer R, Langer K, Mommert S, Wittmann M, Kapp A & Werfel T (2003) Human dendritic cells express the IL-18R and are chemoattracted to IL-18. J Immunol 171, 6363–6371.
10.4049/jimmunol.171.12.6363
CASPubMedWeb of Science®Google Scholar
34Tominaga K, Yoshimoto T, Torigoe K, Kurimoto M, Matsui K, Hada T, Okamura H & Nakanishi K (2000) IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells. Int Immunol 12, 151–160.
10.1093/intimm/12.2.151
CASPubMedWeb of Science®Google Scholar
35Fantuzzi G, Puren AJ, Harding MW, Livingston DJ & Dinarello CA (1998) Interleukin-18 regulation of interferon gamma production and cell proliferation as shown in interleukin-1beta-converting enzyme (caspase-1)-deficient mice. Blood 91, 2118–2125.
10.1182/blood.V91.6.2118
CASPubMedWeb of Science®Google Scholar
36Fantuzzi G, Reed DA & Dinarello CA (1999) IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor. J Clin Investig 104, 761–767.
10.1172/JCI7501
CASPubMedWeb of Science®Google Scholar
37Rank MA, Kobayashi T, Kozaki H, Bartemes KR, Squillace DL & Kita H (2009) IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol 123, 1047–1054.
10.1016/j.jaci.2009.02.026
CASPubMedWeb of Science®Google Scholar
38Su Z, Lin J, Lu F, Zhang X, Zhang L, Gandhi NB, de Paiva CS, Pflugfelder SC & Li DQ (2013) Potential autocrine regulation of interleukin-33/ST2 signaling of dendritic cells in allergic inflammation. Mucosal Immunol 6, 921–930.
10.1038/mi.2012.130
CASPubMedWeb of Science®Google Scholar
39Schwartz C, O'Grady K, Lavelle EC & Fallon PG (2016) Interleukin 33: an innate alarm for adaptive responses beyond Th2 immunity-emerging roles in obesity, intestinal inflammation, and cancer. Eur J Immunol 46, 1091–1100.
10.1002/eji.201545780
CASPubMedWeb of Science®Google Scholar
40Besnard AG, Togbe D, Guillou N, Erard F, Quesniaux V & Ryffel B (2011) IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur J Immunol 41, 1675–1686.
10.1002/eji.201041033
CASPubMedWeb of Science®Google Scholar
41Endo Y, Hirahara K, Iinuma T, Shinoda K, Tumes DJ, Asou HK, Matsugae N, Obata-Ninomiya K, Yamamoto H, Motohashi S et al. (2015) The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity 42, 294–308.
10.1016/j.immuni.2015.01.016
CASPubMedWeb of Science®Google Scholar
42Matta BM, Lott JM, Mathews LR, Liu Q, Rosborough BR, Blazar BR & Turnquist HR (2014) IL-33 is an unconventional Alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2 + regulatory T cells. J Immunol 193, 4010–4020.
10.4049/jimmunol.1400481
CASPubMedWeb of Science®Google Scholar
43Yang Z, Grinchuk V, Urban JF Jr, Bohl J, Sun R, Notari L, Yan S, Ramalingam T, Keegan AD, Wynn TA et al. (2013) Macrophages as IL-25/IL-33-responsive cells play an important role in the induction of type 2 immunity. PLoS One 8, e59441.
10.1371/journal.pone.0059441
CASPubMedWeb of Science®Google Scholar
44Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, Zribi J, Bal E, Cluzeau C, Chrabieh M et al. (2011) Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 365, 620–628.
10.1056/NEJMoa1013068
CASPubMedWeb of Science®Google Scholar
45Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, Mitsuma T, Tsuda K, Nishida E, Togawa Y, Nakajima K et al. (2013) The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Dermatol 133, 2514–2521.
10.1038/jid.2013.230
CASPubMedWeb of Science®Google Scholar
46Tortola L, Rosenwald E, Abel B, Blumberg H, Schafer M, Coyle AJ, Renauld JC, Werner S, Kisielow J & Kopf M (2012) Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Investig 122, 3965–3976.
10.1172/JCI63451
CASPubMedWeb of Science®Google Scholar
47Dietrich D, Martin P, Flacher V, Sun Y, Jarrossay D, Brembilla N, Mueller C, Arnett HA, Palmer G, Towne J et al. (2016) Interleukin-36 potently stimulates human M2 macrophages, Langerhans cells and keratinocytes to produce pro-inflammatory cytokines. Cytokine 84, 88–98.
10.1016/j.cyto.2016.05.012
CASPubMedWeb of Science®Google Scholar
48Mutamba S, Allison A, Mahida Y, Barrow P & Foster N (2012) Expression of IL-1Rrp2 by human myelomonocytic cells is unique to DCs and facilitates DC maturation by IL-1F8 and IL-1F9. Eur J Immunol 42, 607–617.
10.1002/eji.201142035
CASPubMedWeb of Science®Google Scholar
49Higgins J, Mutamba S, Mahida Y, Barrow P & Foster N (2015) IL-36alpha induces maturation of Th1-inducing human MDDC and synergises with IFN-gamma to induce high surface expression of CD14 and CD11c. Hum Immunol 76, 245–253.
10.1016/j.humimm.2015.01.012
CASPubMedWeb of Science®Google Scholar
50Vigne S, Palmer G, Lamacchia C, Martin P, Talabot-Ayer D, Rodriguez E, Ronchi F, Sallusto F, Dinh H, Sims JE et al. (2011) IL-36R ligands are potent regulators of dendritic and T cells. Blood 118, 5813–5823.
10.1182/blood-2011-05-356873
CASPubMedWeb of Science®Google Scholar
51Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P & Dinarello CA (2010) IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 11, 1014–1022.
10.1038/ni.1944
CASPubMedWeb of Science®Google Scholar
52Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A & Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8, 942–949.
10.1038/ni1496
CASPubMedWeb of Science®Google Scholar
53Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q et al. (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587.
10.1016/j.immuni.2009.02.007
CASPubMedWeb of Science®Google Scholar
54Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, Basham B, Smith K, Chen T, Morel F et al. (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8, 950–957.
10.1038/ni1497
CASPubMedWeb of Science®Google Scholar
55Sutton C, Brereton C, Keogh B, Mills KH & Lavelle EC (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203, 1685–1691.
10.1084/jem.20060285
CASPubMedWeb of Science®Google Scholar
56Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S & Watanabe M (2008) MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4 + T cells in chronic colitis. J Immunol 180, 5291–5299.
10.4049/jimmunol.180.8.5291
CASPubMedWeb of Science®Google Scholar
57Ben-Sasson SZ, Hu-Li J, Quiel J, Cauchetaux S, Ratner M, Shapira I, Dinarello CA & Paul WE (2009) IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci USA 106, 7119–7124.
10.1073/pnas.0902745106
CASPubMedWeb of Science®Google Scholar
58Afonina IS, Tynan GA, Logue SE, Cullen SP, Bots M, Luthi AU, Reeves EP, McElvaney NG, Medema JP, Lavelle EC et al. (2011) Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1alpha. Mol Cell 44, 265–278.
10.1016/j.molcel.2011.07.037
CASPubMedWeb of Science®Google Scholar
59Taylor-Robinson AW & Phillips RS (1994) Expression of the IL-1 receptor discriminates Th2 from Th1 cloned CD4 + T cells specific for Plasmodium chabaudi. Immunology 81, 216–221.
CASPubMedWeb of Science®Google Scholar
60Santarlasci V, Cosmi L, Maggi L, Liotta F & Annunziato F (2013) IL-1 and T Helper Immune Responses. Front Immunol 4, 182.
10.3389/fimmu.2013.00182
PubMedWeb of Science®Google Scholar
61Ben-Sasson SZ, Hogg A, Hu-Li J, Wingfield P, Chen X, Crank M, Caucheteux S, Ratner-Hurevich M, Berzofsky JA, Nir-Paz R et al. (2013) IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J Exp Med 210, 491–502.
10.1084/jem.20122006
CASPubMedWeb of Science®Google Scholar
62Ben-Sasson SZ, Wang K, Cohen J & Paul WE (2013) IL-1beta strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb Symp Quant Biol 78, 117–124.
10.1101/sqb.2013.78.021246
CASPubMedGoogle Scholar
63Okamura H, Kashiwamura S, Tsutsui H, Yoshimoto T & Nakanishi K (1998) Regulation of interferon-gamma production by IL-12 and IL-18. Curr Opinion Immunol 10, 259–264.
10.1016/S0952-7915(98)80163-5
CASPubMedWeb of Science®Google Scholar
64Guo L, Wei G, Zhu J, Liao W, Leonard WJ, Zhao K & Paul W (2009) IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci USA 106, 13463–13468.
10.1073/pnas.0906988106
CASPubMedWeb of Science®Google Scholar
65Denton AE, Doherty PC, Turner SJ & La Gruta NL (2007) IL-18, but not IL-12, is required for optimal cytokine production by influenza virus-specific CD8 + T cells. Eur J Immunol 37, 368–375.
10.1002/eji.200636766
CASPubMedWeb of Science®Google Scholar
66Kupz A, Guarda G, Gebhardt T, Sander LE, Short KR, Diavatopoulos DA, Wijburg OL, Cao H, Waithman JC, Chen W et al. (2012) NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8(+) T cells. Nat Immunol 13, 162–169.
10.1038/ni.2195
CASPubMedWeb of Science®Google Scholar
67Soudja SM, Ruiz AL, Marie JC & Lauvau G (2012) Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. Immunity 37, 549–562.
10.1016/j.immuni.2012.05.029
CASPubMedWeb of Science®Google Scholar
68Yang Q, Li G, Zhu Y, Liu L, Chen E, Turnquist H, Zhang X, Finn OJ, Chen X & Lu B (2011) IL-33 synergizes with TCR and IL-12 signaling to promote the effector function of CD8 + T cells. Eur J Immunol 41, 3351–3360.
10.1002/eji.201141629
CASPubMedWeb of Science®Google Scholar
69Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X et al. (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490.
10.1016/j.immuni.2005.09.015
CASPubMedWeb of Science®Google Scholar
70Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB & Liew FY (2007) IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol 37, 2779–2786.
10.1002/eji.200737547
CASPubMedWeb of Science®Google Scholar
71Baumann C, Bonilla WV, Frohlich A, Helmstetter C, Peine M, Hegazy AN, Pinschewer DD & Lohning M (2015) T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proc Natl Acad Sci USA 112, 4056–4061.
10.1073/pnas.1418549112
CASPubMedWeb of Science®Google Scholar
72Bonilla WV, Frohlich A, Senn K, Kallert S, Fernandez M, Johnson S, Kreutzfeldt M, Hegazy AN, Schrick C, Fallon PG et al. (2012) The alarmin interleukin-33 drives protective antiviral CD8(+) T cell responses. Science 335, 984–989.
10.1126/science.1215418
CASPubMedWeb of Science®Google Scholar
73Villarreal DO, Siefert RJ & Weiner DB (2015) Alarmin IL-33 elicits potent TB-specific cell-mediated responses. Hum Vaccin Immunother 11, 1954–1960.
10.1080/21645515.2015.1026499
PubMedWeb of Science®Google Scholar
74Villarreal DO, Wise MC, Walters JN, Reuschel EL, Choi MJ, Obeng-Adjei N, Yan J, Morrow MP & Weiner DB (2014) Alarmin IL-33 acts as an immunoadjuvant to enhance antigen-specific tumor immunity. Can Res 74, 1789–1800.
10.1158/0008-5472.CAN-13-2729
CASPubMedWeb of Science®Google Scholar
75Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S, Lehr HA, Wirtz S, Vieth M, Waisman A et al. (2014) TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 15, 676–686.
10.1038/ni.2920
CASPubMedWeb of Science®Google Scholar
76Schiering C, Krausgruber T, Chomka A, Frohlich A, Adelmann K, Wohlfert EA, Pott J, Griseri T, Bollrath J, Hegazy AN et al. (2014) The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568.
10.1038/nature13577
CASPubMedWeb of Science®Google Scholar
77Li M, Li Y, Liu X, Gao X & Wang Y (2012) IL-33 blockade suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. J Neuroimmunol 247, 25–31.
10.1016/j.jneuroim.2012.03.016
CASPubMedWeb of Science®Google Scholar
78Matta BM & Turnquist HR (2016) Expansion of regulatory T cells in vitro and in vivo by IL-33. Methods Mol Biol 1371, 29–41.
10.1007/978-1-4939-3139-2_3
CASPubMedGoogle Scholar
79Kuswanto W, Burzyn D, Panduro M, Wang KK, Jang YC, Wagers AJ, Benoist C & Mathis D (2016) Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity 44, 355–367.
10.1016/j.immuni.2016.01.009
CASPubMedWeb of Science®Google Scholar
80Vigne S, Palmer G, Martin P, Lamacchia C, Strebel D, Rodriguez E, Olleros ML, Vesin D, Garcia I, Ronchi F et al. (2012) IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4 + T cells. Blood 120, 3478–3487.
10.1182/blood-2012-06-439026
CASPubMedWeb of Science®Google Scholar
81Segueni N, Vigne S, Palmer G, Bourigault ML, Olleros ML, Vesin D, Garcia I, Ryffel B, Quesniaux VF & Gabay C (2015) Limited contribution of IL-36 versus IL-1 and TNF pathways in host response to mycobacterial infection. PLoS One 10, e0126058.
10.1371/journal.pone.0126058
PubMedWeb of Science®Google Scholar
82Tsurutani N, Mittal P, St Rose MC, Ngoi SM, Svedova J, Menoret A, Treadway FB, Laubenbacher R, Suarez-Ramirez JE, Cauley LS et al. (2016) Costimulation endows immunotherapeutic CD8 T cells with IL-36 responsiveness during aerobic glycolysis. J Immunol 196, 124–134.
10.4049/jimmunol.1501217
CASPubMedWeb of Science®Google Scholar
83Harusato A, Abo H, Ngo VL, Yi SW, Mitsutake K, Osuka S, Kohlmeier JE, Li JD, Gewirtz AT, Nusrat A et al. (2017) IL-36gamma signaling controls the induced regulatory T cell-Th9 cell balance via NFkappaB activation and STAT transcription factors. Mucosal Immunol 10, 1455–1467.
10.1038/mi.2017.21
CASPubMedWeb of Science®Google Scholar
84Li H, Nookala S & Re F (2007) Aluminum hydroxide adjuvants activate caspase-1 and induce IL-1beta and IL-18 release. J Immunol 178, 5271–5276.
10.4049/jimmunol.178.8.5271
CASPubMedWeb of Science®Google Scholar
85Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS & Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126.
10.1038/nature06939
CASPubMedWeb of Science®Google Scholar
86Li H, Willingham SB, Ting JP & Re F (2008) Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3. J Immunol 181, 17–21.
10.1111/j.1365-2567.2007.02774.x
CASPubMedWeb of Science®Google Scholar
87Franchi L & Nunez G (2008) The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1beta secretion but dispensable for adjuvant activity. Eur J Immunol 38, 2085–2089.
10.1002/eji.200838549
CASPubMedWeb of Science®Google Scholar
88McKee AS, Munks MW, MacLeod MK, Fleenor CJ, Van Rooijen N, Kappler JW & Marrack P (2009) Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol 183, 4403–4414.
10.4049/jimmunol.0900164
CASPubMedWeb of Science®Google Scholar
89Oleszycka E, Moran HB, Tynan GA, Hearnden CH, Coutts G, Campbell M, Allan SM, Scott CJ & Lavelle EC (2016) IL-1alpha and inflammasome-independent IL-1beta promote neutrophil infiltration following alum vaccination. FEBS J 283, 9–24.
10.1111/febs.13546
CASPubMedWeb of Science®Google Scholar
90Spreafico R, Ricciardi-Castagnoli P & Mortellaro A (2010) The controversial relationship between NLRP3, alum, danger signals and the next-generation adjuvants. Eur J Immunol 40, 638–642.
10.1002/eji.200940039
CASPubMedWeb of Science®Google Scholar
91Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ et al. (2011) DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med 17, 996–1002.
10.1038/nm.2403
CASPubMedWeb of Science®Google Scholar
92Calabro S, Tortoli M, Baudner BC, Pacitto A, Cortese M, O'Hagan DT, De Gregorio E, Seubert A & Wack A (2011) Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine 29, 1812–1823.
10.1016/j.vaccine.2010.12.090
CASPubMedWeb of Science®Google Scholar
93Munks MW, McKee AS, Macleod MK, Powell RL, Degen JL, Reisdorph NA, Kappler JW & Marrack P (2010) Aluminum adjuvants elicit fibrin-dependent extracellular traps in vivo. Blood 116, 5191–5199.
10.1182/blood-2010-03-275529
CASPubMedWeb of Science®Google Scholar
94Seubert A, Monaci E, Pizza M, O'Hagan DT & Wack A (2008) The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells. J Immunol 180, 5402–5412.
10.4049/jimmunol.180.8.5402
CASPubMedWeb of Science®Google Scholar
95McKee AS & Marrack P (2017) Old and new adjuvants. Curr Opin Immunol 47, 44–51.
10.1016/j.coi.2017.06.005
CASPubMedWeb of Science®Google Scholar
96Stephen J, Scales HE, Benson RA, Erben D, Garside P & Brewer JM (2017) Neutrophil swarming and extracellular trap formation play a significant role in Alum adjuvant activity. NPJ Vaccines 2, 1.
10.1038/s41541-016-0001-5
CASPubMedWeb of Science®Google Scholar
97Li P, Li M, Lindberg MR, Kennett MJ, Xiong N & Wang Y (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 207, 1853–1862.
10.1084/jem.20100239
CASPubMedWeb of Science®Google Scholar
98Lu F & Hogenesch H (2013) Kinetics of the inflammatory response following intramuscular injection of aluminum adjuvant. Vaccine 31, 3979–3986.
10.1016/j.vaccine.2013.05.107
CASPubMedWeb of Science®Google Scholar
99Matsushita K & Yoshimoto T (2014) B cell-intrinsic MyD88 signaling is essential for IgE responses in lungs exposed to pollen allergens. J Immunol 193, 5791–5800.
10.4049/jimmunol.1401768
CASPubMedWeb of Science®Google Scholar
100Kuroda E, Ozasa K, Temizoz B, Ohata K, Koo CX, Kanuma T, Kusakabe T, Kobari S, Horie M, Morimoto Y et al. (2016) Inhaled fine particles induce alveolar macrophage death and interleukin-1alpha release to promote inducible bronchus-associated lymphoid tissue formation. Immunity 45, 1299–1310.
10.1016/j.immuni.2016.11.010
CASPubMedWeb of Science®Google Scholar
101Rose WA II, Okragly AJ, Patel CN & Benschop RJ (2015) IL-33 released by alum is responsible for early cytokine production and has adjuvant properties. Sci Rep 5, 13146.
10.1038/srep13146
CASPubMedWeb of Science®Google Scholar
102Gavin AL, Hoebe K, Duong B, Ota T, Martin C, Beutler B & Nemazee D (2006) Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science 314, 1936–1938.
10.1126/science.1135299
CASPubMedWeb of Science®Google Scholar
103Schnare M, Barton GM, Holt AC, Takeda K, Akira S & Medzhitov R (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2, 947–950.
10.1038/ni712
CASPubMedWeb of Science®Google Scholar
104Palomo J, Dietrich D, Martin P, Palmer G & Gabay C (2015) The interleukin (IL)-1 cytokine family–Balance between agonists and antagonists in inflammatory diseases. Cytokine 76, 25–37.
10.1016/j.cyto.2015.06.017
CASPubMedWeb of Science®Google Scholar
105Casella CR & Mitchell TC (2008) Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell Mol Life Sci 65, 3231–3240.
10.1007/s00018-008-8228-6
CASPubMedWeb of Science®Google Scholar
106Didierlaurent AM, Morel S, Lockman L, Giannini SL, Bisteau M, Carlsen H, Kielland A, Vosters O, Vanderheyde N, Schiavetti F et al. (2009) AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 183, 6186–6197.
10.4049/jimmunol.0901474
CASPubMedWeb of Science®Google Scholar
107Embry CA, Franchi L, Nunez G & Mitchell TC (2011) Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A. Sci Signal 4, ra28.
10.1126/scisignal.2001486
CASPubMedWeb of Science®Google Scholar
108Fox CB & Haensler J (2013) An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants. Expert Rev Vaccines 12, 747–758.
10.1586/14760584.2013.811188
CASPubMedWeb of Science®Google Scholar
109Galli G, Medini D, Borgogni E, Zedda L, Bardelli M, Malzone C, Nuti S, Tavarini S, Sammicheli C, Hilbert AK et al. (2009) Adjuvanted H5N1 vaccine induces early CD4 + T cell response that predicts long-term persistence of protective antibody levels. Proc Natl Acad Sci USA 106, 3877–3882.
10.1073/pnas.0813390106
CASPubMedWeb of Science®Google Scholar
110Vono M, Taccone M, Caccin P, Gallotta M, Donvito G, Falzoni S, Palmieri E, Pallaoro M, Rappuoli R, Di Virgilio F et al. (2013) The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination. Proc Natl Acad Sci USA 110, 21095–21100.
10.1073/pnas.1319784110
CASPubMedWeb of Science®Google Scholar
111Piccini A, Carta S, Tassi S, Lasiglie D, Fossati G & Rubartelli A (2008) ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1beta and IL-18 secretion in an autocrine way. Proc Natl Acad Sci USA 105, 8067–8072.
10.1073/pnas.0709684105
CASPubMedWeb of Science®Google Scholar
112Riteau N, Baron L, Villeret B, Guillou N, Savigny F, Ryffel B, Rassendren F, Le Bert M, Gombault A & Couillin I (2012) ATP release and purinergic signaling: a common pathway for particle-mediated inflammasome activation. Cell Death Dis 3, e403.
10.1038/cddis.2012.144
CASPubMedWeb of Science®Google Scholar
113Ellebedy AH, Lupfer C, Ghoneim HE, DeBeauchamp J, Kanneganti TD & Webby RJ (2011) Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59. Proc Natl Acad Sci USA 108, 2927–2932.
10.1073/pnas.1012455108
CASPubMedWeb of Science®Google Scholar
114Seubert A, Calabro S, Santini L, Galli B, Genovese A, Valentini S, Aprea S, Colaprico A, D'Oro U, Giuliani MM et al. (2011) Adjuvanticity of the oil-in-water emulsion MF59 is independent of Nlrp3 inflammasome but requires the adaptor protein MyD88. Proc Natl Acad Sci USA 108, 11169–11174.
10.1073/pnas.1107941108
CASPubMedWeb of Science®Google Scholar
115Webby RJ (2013) Correction for Ellebedy et al., Inflammasome-independent role of the apoptosis-associated speck-like protein containing CARD (ASC) in the adjuvant effect of MF59. Proc Natl Acad Sci 110, 4429.
10.1073/pnas.1301192110
Web of Science®Google Scholar
116Ippagunta SK, Malireddi RK, Shaw PJ, Neale GA, Vande Walle L, Fukui Y, Green DR, Lamkanfi M & Kanneganti TD (2012) Addendum: defective Dock2 expression in a subset of ASC-deficient mouse lines. Nat Immunol 13, 701–702.
10.1038/ni.2389
CASPubMedWeb of Science®Google Scholar
117Calven J, Akbarshahi H, Menzel M, Ayata CK, Idzko M, Bjermer L & Uller L (2015) Rhinoviral stimuli, epithelial factors and ATP signalling contribute to bronchial smooth muscle production of IL-33. J Transl Med 13, 281.
10.1186/s12967-015-0645-3
PubMedWeb of Science®Google Scholar
118Desbien AL, Reed SJ, Bailor HR, Dubois Cauwelaert N, Laurance JD, Orr MT, Fox CB, Carter D, Reed SG & Duthie MS (2015) Squalene emulsion potentiates the adjuvant activity of the TLR4 agonist, GLA, via inflammatory caspases, IL-18, and IFN-gamma. Eur J Immunol 45, 407–417.
10.1002/eji.201444543
CASPubMedWeb of Science®Google Scholar
119Dubois Cauwelaert N, Desbien AL, Hudson TE, Pine SO, Reed SG, Coler RN & Orr MT (2016) The TLR4 agonist vaccine adjuvant, GLA-SE, requires canonical and atypical mechanisms of action for TH1 induction. PLoS One 11, e0146372.
PubMedWeb of Science®Google Scholar
120Orr MT, Duthie MS, Windish HP, Lucas EA, Guderian JA, Hudson TE, Shaverdian N, O'Donnell J, Desbien AL, Reed SG et al. (2013) MyD88 and TRIF synergistic interaction is required for TH1-cell polarization with a synthetic TLR4 agonist adjuvant. Eur J Immunol 43, 2398–2408.
10.1002/eji.201243124
CASPubMedWeb of Science®Google Scholar
121Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, Planty C, Elouahabi A, Harvengt P, Carlsen H et al. (2011) Adjuvant System AS03 containing alpha-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 29, 2461–2473.
10.1016/j.vaccine.2011.01.011
CASPubMedWeb of Science®Google Scholar
122Marty-Roix R, Vladimer GI, Pouliot K, Weng D, Buglione-Corbett R, West K, MacMicking JD, Chee JD, Wang S, Lu S et al. (2016) Identification of QS-21 as an inflammasome-activating molecular component of saponin adjuvants. J Biol Chem 291, 1123–1136.
10.1074/jbc.M115.683011
CASPubMedWeb of Science®Google Scholar
123Didierlaurent AM, Laupeze B, Di Pasquale A, Hergli N, Collignon C & Garcon N (2017) Adjuvant system AS01: helping to overcome the challenges of modern vaccines. Expert Rev Vaccines 16, 55–63.
10.1080/14760584.2016.1213632
CASPubMedWeb of Science®Google Scholar
124Wilson NS, Duewell P, Yang B, Li Y, Marsters S, Koernig S, Latz E, Maraskovsky E, Morelli AB, Schnurr M et al. (2014) Inflammasome-dependent and -independent IL-18 production mediates immunity to the ISCOMATRIX adjuvant. J Immunol 192, 3259–3268.
10.4049/jimmunol.1302011
CASPubMedWeb of Science®Google Scholar
125Knudsen NP, Olsen A, Buonsanti C, Follmann F, Zhang Y, Coler RN, Fox CB, Meinke A, D'Oro U, Casini D et al. (2016) Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens. Sci Rep 6, 19570.
10.1038/srep19570
CASPubMedWeb of Science®Google Scholar
126Desel C, Werninghaus K, Ritter M, Jozefowski K, Wenzel J, Russkamp N, Schleicher U, Christensen D, Wirtz S, Kirschning C et al. (2013) The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling. PLoS One 8, e53531.
10.1371/journal.pone.0053531
CASPubMedWeb of Science®Google Scholar
127Schoenen H, Bodendorfer B, Hitchens K, Manzanero S, Werninghaus K, Nimmerjahn F, Agger EM, Stenger S, Andersen P, Ruland J et al. (2010) Cutting edge: mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. J Immunol 184, 2756–2760.
10.4049/jimmunol.0904013
CASPubMedWeb of Science®Google Scholar
128Bueter CL, Lee CK, Wang JP, Ostroff GR, Specht CA & Levitz SM (2014) Spectrum and mechanisms of inflammasome activation by chitosan. J Immunol 192, 5943–5951.
10.4049/jimmunol.1301695
CASPubMedWeb of Science®Google Scholar
129Mori A, Oleszycka E, Sharp FA, Coleman M, Ozasa Y, Singh M, O'Hagan DT, Tajber L, Corrigan OI, McNeela EA et al. (2012) The vaccine adjuvant alum inhibits IL-12 by promoting PI3 kinase signaling while chitosan does not inhibit IL-12 and enhances Th1 and Th17 responses. Eur J Immunol 42, 2709–2719.
10.1002/eji.201242372
CASPubMedWeb of Science®Google Scholar
130Carroll EC, Jin L, Mori A, Munoz-Wolf N, Oleszycka E, Moran HBT, Mansouri S, McEntee CP, Lambe E, Agger EM et al. (2016) The vaccine adjuvant chitosan promotes cellular immunity via DNA Sensor cGAS-STING-dependent induction of type I interferons. Immunity 44, 597–608.
10.1016/j.immuni.2016.02.004
CASPubMedWeb of Science®Google Scholar
131Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Forster I, Farlik M, Decker T, Du Pasquier RA, Romero P et al. (2011) Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity 34, 213–223.
10.1016/j.immuni.2011.02.006
CASPubMedWeb of Science®Google Scholar
132Nakae S, Komiyama Y, Yokoyama H, Nambu A, Umeda M, Iwase M, Homma I, Sudo K, Horai R, Asano M et al. (2003) IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int Immunol 15, 483–490.
10.1093/intimm/dxg054
CASPubMedWeb of Science®Google Scholar
133Xu D, Trajkovic V, Hunter D, Leung BP, Schulz K, Gracie JA, McInnes IB & Liew FY (2000) IL-18 induces the differentiation of Th1 or Th2 cells depending upon cytokine milieu and genetic background. Eur J Immunol 30, 3147–3156.
10.1002/1521-4141(200011)30:11<3147::AID-IMMU3147>3.0.CO;2-J
CASPubMedWeb of Science®Google Scholar
134Gresnigt MS & van de Veerdonk FL (2013) Biology of IL-36 cytokines and their role in disease. Semin Immunol 25, 458–465.
10.1016/j.smim.2013.11.003
CASPubMedWeb of Science®Google Scholar
135Aaes TL, Kaczmarek A, Delvaeye T, De Craene B, De Koker S, Heyndrickx L, Delrue I, Taminau J, Wiernicki B, De Groote P et al. (2016) Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep 15, 274–287.
10.1016/j.celrep.2016.03.037
CASPubMedWeb of Science®Google Scholar
136Rumbo M, Carnoy C & Sirard JC (2017) Chapter 7 - Flagellins as adjuvants of vaccines A2 - Schijns, Virgil E.J.C. In Immunopotentiators in Modern Vaccines, 2nd edn. ( DT O'Hagan, ed), pp. 129–147. Academic Press, NY.
10.1016/B978-0-12-804019-5.00007-4
Google Scholar
137Sciorati C, Rigamonti E, Manfredi AA & Rovere-Querini P (2016) Cell death, clearance and immunity in the skeletal muscle. Cell Death Differ 23, 927–937.
10.1038/cdd.2015.171
CASPubMedWeb of Science®Google Scholar
138Lima H Jr, Jacobson LS, Goldberg MF, Chandran K, Diaz-Griffero F, Lisanti MP & Brojatsch J (2013) Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death. Cell Cycle 12, 1868–1878.
10.4161/cc.24903
CASPubMedWeb of Science®Google Scholar
139Jacobson LS, Lima H Jr, Goldberg MF, Gocheva V, Tsiperson V, Sutterwala FS, Joyce JA, Gapp BV, Blomen VA, Chandran K et al. (2013) Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants. J Biol Chem 288, 7481–7491.
10.1074/jbc.M112.400655
CASPubMedWeb of Science®Google Scholar
140Wu CA & Yang YW (2004) Induction of cell death by saponin and antigen delivery. Pharm Res 21, 271–277.
10.1023/B:PHAM.0000016239.04067.66
CASPubMedWeb of Science®Google Scholar
141Yang YW, Wu CA & Morrow WJ (2004) Cell death induced by vaccine adjuvants containing surfactants. Vaccine 22, 1524–1536.
10.1016/j.vaccine.2003.08.048
CASPubMedWeb of Science®Google Scholar
142Lian LH, Milora KA, Manupipatpong KK & Jensen LE (2015) The double-stranded RNA analogue polyinosinic-polycytidylic acid induces keratinocyte pyroptosis and release of IL-36gamma. J Invest Dermatol 132, 1346–1353.
10.1038/jid.2011.482
Web of Science®Google Scholar
143Broz P & Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 16, 407–420.
10.1038/nri.2016.58
CASPubMedWeb of Science®Google Scholar
144England H, Summersgill HR, Edye ME, Rothwell NJ & Brough D (2014) Release of interleukin-1alpha or interleukin-1beta depends on mechanism of cell death. J Biol Chem 289, 15942–15950.
10.1074/jbc.M114.557561
CASPubMedWeb of Science®Google Scholar
145Lukens JR, Vogel P, Johnson GR, Kelliher MA, Iwakura Y, Lamkanfi M & Kanneganti TD (2013) RIP1-driven autoinflammation targets IL-1alpha independently of inflammasomes and RIP3. Nature 498, 224–227.
10.1038/nature12174
CASPubMedWeb of Science®Google Scholar
146Kayamuro H, Yoshioka Y, Abe Y, Arita S, Katayama K, Nomura T, Yoshikawa T, Kubota-Koketsu R, Ikuta K, Okamoto S et al. (2010) Interleukin-1 family cytokines as mucosal vaccine adjuvants for induction of protective immunity against influenza virus. J Virol 84, 12703–12712.
10.1128/JVI.01182-10
CASPubMedWeb of Science®Google Scholar
147Staats HF, Bradney CP, Gwinn WM, Jackson SS, Sempowski GD, Liao HX, Letvin NL & Haynes BF (2001) Cytokine requirements for induction of systemic and mucosal CTL after nasal immunization. J Immunol 167, 5386–5394.
10.4049/jimmunol.167.9.5386
CASPubMedWeb of Science®Google Scholar
148Kono H & Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8, 279–289.
10.1038/nri2215
CASPubMedWeb of Science®Google Scholar
149Nace G, Evankovich J, Eid R & Tsung A (2012) Dendritic cells and damage-associated molecular patterns: endogenous danger signals linking innate and adaptive immunity. J Innate Immun 4, 6–15.
10.1159/000334245
CASPubMedWeb of Science®Google Scholar
150Land W (2003) Allograft injury mediated by reactive oxygen species: from conserved proteins of Drosophila to acute and chronic rejection of human transplants. Part III: interaction of (oxidative) stress-induced heat shock proteins with toll-like receptor-bearing cells of innate immunity and its consequences for the development of acute and chronic allograft rejection. Transplant Rev 17, 67–86.
10.1016/S0955-470X(02)00009-5
Google Scholar
151Schijns VE & Lavelle EC (2011) Trends in vaccine adjuvants. Expert Rev Vaccines 10, 539–550.
10.1586/erv.11.21
CASPubMedWeb of Science®Google Scholar
152Rappuoli R, Mandl CW, Black S & De Gregorio E (2011) Vaccines for the twenty-first century society. Nat Rev Immunol 11, 865–872.
10.1038/nri3085
CASPubMedWeb of Science®Google Scholar
153Grover A, Troudt J, Foster C, Basaraba R & Izzo A (2014) High mobility group box 1 acts as an adjuvant for tuberculosis subunit vaccines. Immunology 142, 111–123.
10.1111/imm.12236
CASPubMedWeb of Science®Google Scholar
154McKee AS, Burchill MA, Munks MW, Jin L, Kappler JW, Friedman RS, Jacobelli J & Marrack P (2013) Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. Proc Natl Acad Sci USA 110, E1122–E1131.
10.1073/pnas.1300392110
CASPubMedWeb of Science®Google Scholar
155Zhu Q & Kanneganti TD (2017) Cutting Edge: distinct regulatory mechanisms control proinflammatory cytokines IL-18 and IL-1beta. J Immunol 198, 4210–4215.
10.4049/jimmunol.1700352
CASPubMedWeb of Science®Google Scholar
156Luthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, Brumatti G, Taylor RC, Kersse K, Vandenabeele P et al. (2009) Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98.
10.1016/j.immuni.2009.05.007
CASPubMedWeb of Science®Google Scholar
157Cayrol C & Girard JP (2009) The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc Natl Acad Sci USA 106, 9021–9026.
10.1073/pnas.0812690106
CASPubMedWeb of Science®Google Scholar
158Gabay C & Towne JE (2014) Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions. J Leukoc Biol 97, 645–652.
10.1189/jlb.3RI1014-495R
Web of Science®Google Scholar
159Macleod T, Doble R, McGonagle D, Wasson CW, Alase A, Stacey M & Wittmann M (2016) Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 Receptor antagonist. Sci Rep 6, 24880.
10.1038/srep24880
CASPubMedWeb of Science®Google Scholar
160Nold-Petry CA, Lo CY, Rudloff I, Elgass KD, Li S, Gantier MP, Lotz-Havla AS, Gersting SW, Cho SX, Lao JC et al. (2015) IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat Immunol 16, 354–365.
10.1038/ni.3103
CASPubMedWeb of Science®Google Scholar
161Kumar S, Hanning CR, Brigham-Burke MR, Rieman DJ, Lehr R, Khandekar S, Kirkpatrick RB, Scott GF, Lee JC, Lynch FJ et al. (2002) Interleukin-1F7B (IL-1H4/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 18, 61–71.
10.1006/cyto.2002.0873
CASPubMedWeb of Science®Google Scholar
162Conti P, Carinci F, Lessiani G, Spinas E, Kritas SK, Ronconi G, Caraffa A & Theoharides TC (2017) Potential therapeutic use of IL-37: a key suppressor of innate immunity and allergic immune responses mediated by mast cells. Immunol Res 65, 982–986.
10.1007/s12026-017-8938-7
CASPubMedWeb of Science®Google Scholar
163Mora J, Schlemmer A, Wittig I, Richter F, Putyrski M, Frank AC, Han Y, Jung M, Ernst A, Weigert A et al. (2017) Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses. J Mol Cell Biol 8, 426–438.
10.1093/jmcb/mjw006
Web of Science®Google Scholar
164Yuan X, Peng X, Li Y & Li M (2015) Role of IL-38 and its related cytokines in inflammation. Mediators Inflamm 2015, 807976.
10.1155/2015/807976
CASPubMedWeb of Science®Google Scholar
165Bulau AM, Nold MF, Li S, Nold-Petry CA, Fink M, Mansell A, Schwerd T, Hong J, Rubartelli A, Dinarello CA et al. (2014) Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses. Proc Natl Acad Sci USA 111, 2650–2655.
10.1073/pnas.1324140111
CASPubMedWeb of Science®Google Scholar
166Eng NF, Bhardwaj N, Mulligan R & Diaz-Mitoma F (2013) The potential of 1018 ISS adjuvant in hepatitis B vaccines: HEPLISAV review. Hum Vaccin Immunother 9, 1661–1672.
10.4161/hv.24715
CASPubMedWeb of Science®Google Scholar

Citing Literature

Volume285, Issue13

July 2018

Pages 2377-2401

This article also appears in:

A Guide To...

Journal list menu

Tools

Follow journal

A Guide to IL-1 family cytokines in adjuvanticity