A fundamental concept in immunology is that the innate immune system initiates or instructs downstream adaptive immune responses. Inflammasomes are central players in innate immunity to pathogens, but how inflammasomes shape adaptive immunity is complex and relatively poorly understood. Here we highlight recent work on the interplay between inflammasomes and adaptive immunity. We address how inflammasome-dependent release of cytokines and antigen activates, shapes or even inhibits adaptive immune responses. We consider how distinct tissue or cellular contexts may alter the effects of inflammasome activation on adaptive immunity and how this contributes to beneficial or detrimental outcomes in infectious diseases, cancer and autoimmunity. We aspire to provide a framework for thinking about inflammasomes and their connection to the adaptive immune response.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).
Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343–353 (2015).
Curtsinger, J. M. & Mescher, M. F. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 22, 333–340 (2010).
Jain, A. & Pasare, C. Innate control of adaptive immunity: beyond the three-signal paradigm. J. Immunol. 198, 3791–3800 (2017).
Cyster, J. G. & Allen, C. D. C. B cell responses: cell interaction dynamics and decisions. Cell 177, 524–540 (2019).
Evavold, C. L. & Kagan, J. C. How inflammasomes inform adaptive immunity. J. Mol. Biol. 430, 217–237 (2018).
Rathinam, V. A. K. & Fitzgerald, K. A. Inflammasome complexes: emerging mechanisms and effector functions. Cell 165, 792–800 (2016).
Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Masumoto, J. et al. ASC is an activating adaptor for NF-κB and caspase-8-dependent apoptosis. Biochem. Biophys. Res. Commun. 303, 69–73 (2003).
Man, S. M. et al. Salmonella infection induces recruitment of caspase-8 to the inflammasome to modulate IL-1β production. J. Immunol. 191, 5239–5246 (2013).
Antonopoulos, C. et al. Caspase-8 as an effector and regulator of NLRP3 inflammasome signaling. J. Biol. Chem. 290, 20167–20184 (2015).
Karki, R. et al. Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection. Cell Host Microbe 17, 357–368 (2015).
Goncalves, A. V. et al. Gasdermin-D and caspase-7 are the key caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of Legionella pneumophila. PLoS Pathog. 15, e1007886 (2019).
Rauch, I. et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL-18 release via activation of caspase-1 and -8. Immunity 46, 649–659 (2017).
Schneider, K. S. et al. The inflammasome drives GSDMD-independent secondary pyroptosis and IL-1 release in the absence of caspase-1 protease activity. Cell Rep. 21, 3846–3859 (2017).
Chen, K. W. et al. Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly. EMBO J. 38, e101638 (2019).
Sarhan, J. et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl Acad. Sci. USA 115, E10888–E10897 (2018).
Orning, P. et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 362, 1064–1069 (2018).
Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).
Kajiwara, Y. et al. A critical role for human caspase-4 in endotoxin sensitivity. J. Immunol. 193, 335–343 (2014).
Hagar, J. A., Powell, D. A., Aachoui, Y., Ernst, R. K. & Miao, E. A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 1250–1253 (2013).
Pilla, D. M. et al. Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS. Proc. Natl Acad. Sci. USA 111, 6046–6051 (2014).
Santos, J. C. et al. LPS targets host guanylate-binding proteins to the bacterial outer membrane for non-canonical inflammasome activation. EMBO J. 37, e98089 (2018).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Bibo-Verdugo, B., Snipas, S. J., Kolt, S., Poreba, M. & Salvesen, G. S. Extended subsite profiling of the pyroptosis effector protein gasdermin D reveals a region recognized by inflammatory caspase-11. J. Biol. Chem. 295, 11292–11302 (2020).
Ramirez, M. L. G. et al. Extensive peptide and natural protein substrate screens reveal that mouse caspase-11 has much narrower substrate specificity than caspase-1. J. Biol. Chem. 293, 7058–7067 (2018).
Santos, J. C. et al. Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria. Nat. Commun. 11, 3276 (2020).
Wandel, M. P. et al. Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms. Nat. Immunol. 21, 880–891 (2020).
Yi, Y.-S. Functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes during infection-mediated inflammation. Immunology 159, 142–155 (2020).
de Vasconcelos, N. M. & Lamkanfi, M. Recent insights on inflammasomes, gasdermin pores, and pyroptosis. Cold Spring Harb. Perspect. Biol. 12, a036392 (2020).
Lamkanfi, M. et al. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J. Immunol. 185, 4385–4392 (2010).
von Moltke, J. et al. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490, 107–111 (2012).
de Vasconcelos, N. M., Van Opdenbosch, N., Van Gorp, H., Parthoens, E. & Lamkanfi, M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. 26, 146–161 (2019).
Netea, M. G., van de Veerdonk, F. L., van der Meer, J. W. M., Dinarello, C. A. & Joosten, L. A. B. Inflammasome-independent regulation of IL-1-family cytokines. Annu. Rev. Immunol. 33, 49–77 (2015).
DiPeso, L., Ji, D. X., Vance, R. E. & Price, J. V. Cell death and cell lysis are separable events during pyroptosis. Cell Death Discov. 3, 17070 (2017).
Gutiérrez-Martínez, E. et al. Cross-presentation of cell-associated antigens by MHC class I in dendritic cell subsets. Front. Immunol. 6, 363 (2015).
Gaidt, M. M. et al. Human monocytes engage an alternative inflammasome pathway. Immunity 44, 833–846 (2016).
Evavold, C. L. et al. The pore-forming protein gasdermin D regulates interleukin-1 secretion from living macrophages. Immunity 48, 35–44.e6 (2018).
Chen, K. W. et al. The neutrophil NLRC4 inflammasome selectively promotes IL-1β maturation without pyroptosis during acute Salmonella challenge. Cell Rep. 8, 570–582 (2014).
Jorgensen, I., Zhang, Y., Krantz, B. A. & Miao, E. A. Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J. Exp. Med. 213, 2113–2128 (2016).
Jorgensen, I., Lopez, J. P., Laufer, S. A. & Miao, E. A. IL-1β, IL-18, and eicosanoids promote neutrophil recruitment to pore-induced intracellular traps following pyroptosis. Eur. J. Immunol. 46, 2761–2766 (2016).
Davis, M. A. et al. Calpain drives pyroptotic vimentin cleavage, intermediate filament loss, and cell rupture that mediates immunostimulation. Proc. Natl Acad. Sci. USA 116, 5061–5070 (2019).
Boada-Romero, E., Martinez, J., Heckmann, B. L. & Green, D. R. The clearance of dead cells by efferocytosis. Nat. Rev. Mol. Cell Biol. 21, 398–414 (2020).
Cruz, F. M., Colbert, J. D., Merino, E., Kriegsman, B. A. & Rock, K. L. The biology and underlying mechanisms of cross-presentation of exogenous antigens on MHC-I molecules. Annu. Rev. Immunol. 35, 149–176 (2017).
Cummings, R. J. et al. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539, 565–569 (2016).
Penteado, L. A. et al. Distinctive role of efferocytosis in dendritic cell maturation and migration in sterile or infectious conditions. Immunology 151, 304–313 (2017).
Torchinsky, M. B., Garaude, J., Martin, A. P. & Blander, J. M. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature 458, 78–82 (2009).
Ahrens, S. et al. F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36, 635–645 (2012).
Schulz, O. et al. Myosin II synergizes with F-actin to promote DNGR-1-dependent cross-presentation of dead cell-associated antigens. Cell Rep. 24, 419–428 (2018).
Zelenay, S. et al. The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J. Clin. Invest. 122, 1615–1627 (2012).
Zhang, J.-G. et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity 36, 646–657 (2012).
Theisen, E. & Sauer, J.-D. Listeria monocytogenes-induced cell death inhibits the generation of cell-mediated immunity. Infect. Immun. 85, e00733–16 (2017). By comparing wild-type L. monocytogenes with a flagellin-secreting strain that robustly activates NAIP–NLRC4, this study shows that inflammasome activation during Listeria infection induces a higher number of mature cDC1s. However, the flagellin-secreting strain also resulted in an impaired CD8+ T cell response as compared to the wild-type Listeria.
Pang, I. K., Ichinohe, T. & Iwasaki, A. IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8+ T cell responses to influenza A virus. Nat. Immunol. 14, 246–253 (2013).
Li, J. et al. Induction of dendritic cell maturation by IL-18. Cell Immunol. 227, 103–108 (2004).
Sauer, J.-D. et al. Listeria monocytogenes engineered to activate the Nlrc4 inflammasome are severely attenuated and are poor inducers of protective immunity. Proc. Natl Acad. Sci. USA 108, 12419–12424 (2011).
Cerovic, V. et al. Lymph-borne CD8α+ dendritic cells are uniquely able to cross-prime CD8+ T cells with antigen acquired from intestinal epithelial cells. Mucosal Immunol. 8, 38–48 (2015).
Lei-Leston, A. C., Murphy, A. G. & Maloy, K. J. Epithelial cell inflammasomes in intestinal immunity and inflammation. Front. Immunol. 8, 1168 (2017).
Winsor, N., Krustev, C., Bruce, J., Philpott, D. J. & Girardin, S. E. Canonical and noncanonical inflammasomes in intestinal epithelial cells. Cell Microbiol. 21, e13079 (2019).
Nordlander, S., Pott, J. & Maloy, K. J. NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen. Mucosal Immunol. 7, 775–785 (2014).
Sellin, M. E. et al. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 16, 237–248 (2014).
Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009).
Deng, J., Yu, X.-Q. & Wang, P.-H. Inflammasome activation and Th17 responses. Mol. Immunol. 107, 142–164 (2019).
Dostert, C., Ludigs, K. & Guarda, G. Innate and adaptive effects of inflammasomes on T cell responses. Curr. Opin. Immunol. 25, 359–365 (2013).
Harrison, O. J. et al. Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine. Mucosal Immunol. 8, 1226–1236 (2015).
Mantovani, A., Dinarello, C. A., Molgora, M. & Garlanda, C. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50, 778–795 (2019).
Yasuda, K., Nakanishi, K. & Tsutsui, H. Interleukin-18 in health and disease. Int. J. Mol. Sci. 20, 649 (2019).
Jain, A., Song, R., Wakeland, E. K. & Pasare, C. T cell-intrinsic IL-1R signaling licenses effector cytokine production by memory CD4 T cells. Nat. Commun. 9, 3185 (2018).
Pham, O. H. et al. T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria. PLoS Pathog. 13, e1006566 (2017).
Srinivasan, A. et al. Innate immune activation of CD4 T cells in Salmonella-infected mice is dependent on IL-18. J. Immunol. 178, 6342–6349 (2007).
Aachoui, Y. et al. Caspase-11 protects against bacteria that escape the vacuole. Science 339, 975–978 (2013).
Broz, P. et al. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J. Exp. Med. 207, 1745–1755 (2010).
McSorley, S. J. Immunity to intestinal pathogens: lessons learned from Salmonella. Immunol. Rev. 260, 168–182 (2014).
O'Donnell, H. et al. Toll-like receptor and inflammasome signals converge to amplify the innate bactericidal capacity of T helper 1 cells. Immunity 40, 213–224 (2014). This study was one of the first to demonstrate that mice deficient in both NAIP–NLRC4 and NLRP3 have suppressed non-cognate CD4+ and CD8+ T cell responses as compared to wild-type mice following intravenous Salmonella infection.
Tourlomousis, P. et al. Modifying bacterial flagellin to evade Nod-like receptor CARD 4 recognition enhances protective immunity against. Salmonella. Nat. Microbiol. 5, 1588–1597 (2020). This study shows that NAIP–NLRC4 activation impairs CD4+ T cell immunity during primary and secondary intravenous Salmonella infection. The authors propose a model whereby NAIP–NLRC4 activation prevents robust activation of the NLRP3 inflammasome and thereby limits TH1-driven IL-18 production.
Trunk, G. & Oxenius, A. Innate instruction of CD4+ T cell immunity in respiratory bacterial infection. J. Immunol. 189, 616–628 (2012). This study shows that caspase-1 and IL-1R signaling play a role in TH17 development following intranasal Legionella infection.
Pedra, J. H. F. et al. ASC/PYCARD and caspase-1 regulate the IL-18/IFN-γ axis during Anaplasma phagocytophilum infection. J. Immunol. 179, 4783–4791 (2007).
Ichinohe, T., Lee, H. K., Ogura, Y., Flavell, R. & Iwasaki, A. Inflammasome recognition of influenza virus is essential for adaptive immune responses. J. Exp. Med. 206, 79–87 (2009).
van de Veerdonk, F. L., Joosten, L. A. B. & Netea, M. G. The interplay between inflammasome activation and antifungal host defense. Immunol. Rev. 265, 172–180 (2015).
Feriotti, C. et al. NOD-like receptor P3 inflammasome controls protective Th1/Th17 immunity against pulmonary paracoccidioidomycosis. Front. Immunol. 8, 786 (2017).
Ketelut-Carneiro, N. et al. IL-18 triggered by the Nlrp3 inflammasome induces host innate resistance in a pulmonary model of fungal infection. J. Immunol. 194, 4507–4517 (2015).
Ketelut-Carneiro, N. et al. Caspase-11-dependent IL-1α release boosts Th17 immunity against Paracoccidioides brasiliensis. PLoS Pathog. 15, e1007990 (2019).
Engwerda, C. R., Ng, S. S. & Bunn, P. T. The regulation of CD4+ T cell responses during protozoan infections. Front. Immunol. 5, 498 (2014).
Zamboni, D. S. & Lima-Junior, D. S. Inflammasomes in host response to protozoan parasites. Immunol. Rev. 265, 156–171 (2015).
Silva, G. K. et al. Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1β response and host resistance to Trypanosoma cruzi infection. J. Immunol. 191, 3373–3383 (2013).
Paroli, A. F. et al. NLRP3 inflammasome and caspase-1/11 pathway orchestrate different outcomes in the host protection against Trypanosoma cruzi acute infection. Front. Immunol. 9, 913 (2018).
Gao, Y. et al. Transcriptional profiling identifies caspase-1 as a T cell–intrinsic regulator of Th17 differentiation. J. Exp. Med. 217, e20190476 (2020).
Rostami, A. et al. The role of Blastocystis sp. and Dientamoeba fragilis in irritable bowel syndrome: a systematic review and meta-analysis. Parasitol. Res. 116, 2361–2371 (2017).
Chudnovskiy, A. et al. Host-protozoan interactions protect from mucosal infections through activation of the inflammasome. Cell 167, 444–456.e14 (2016). This study shows that intestinal TH1 and TH17 immunity associated with the parasite T. musculis depends on IL-18 produced by hematopoietic-derived cells. Similarly, ASC is required for a TH1 response following T. musculis colonization.
Cox, M. A., Kahan, S. M. & Zajac, A. J. Anti-viral CD8 T cells and the cytokines that they love. Virology 435, 157–169 (2013).
Kupz, A. et al. NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells. Nat. Immunol. 13, 162–169 (2012). This study was one of the first to show a link between NAIP–NLRC4 activation in dendritic cells and IFN-γ production by non-cognate memory CD8+ T cells following infection with a variety of intracellular bacterial pathogens.
Erlich, Z. et al. Macrophages, rather than DCs, are responsible for inflammasome activity in the GM-CSF BMDC model. Nat. Immunol. 20, 397–406 (2019).
McDaniel, M. M., Kottyan, L. C., Singh, H. & Pasare, C. Suppression of inflammasome activation by IRF8 and IRF4 in cDCs Is critical for T cell priming. Cell Rep. 31, 107604 (2020). In support of the idea that inflammasome activation and subsequent pyroptosis in APCs can be detrimental to mounting a Tcell response, this study shows that transcription factors IRF8 and IRF4 suppress activation of several inflammasome components in cDC1s and cDC2s, respectively. Irf8+/- haploinsufficiency results in a clear reduction of activated CD8+ T cells as compared to Irf8+/+ cells following in vitro Salmonella infection.
Ichinohe, T., Pang, I. K. & Iwasaki, A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol. 11, 404–410 (2010).
Zhang, H. et al. AIM2 inflammasome is critical for influenza-induced lung injury and mortality. J. Immunol. 198, 4383–4393 (2017).
Thomas, P. G. et al. The intracellular sensor NLRP3 mediates key innate and healing responses to influenza A virus via the regulation of caspase-1. Immunity 30, 566–575 (2009).
Allen, I. C. et al. The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity 30, 556–565 (2009).
Lee, P. H. et al. Induction of memory cytotoxic T cells to influenza A virus and subsequent viral clearance is not modulated by PB1-F2-dependent inflammasome activation. Immunol. Cell Biol. 94, 439–446 (2016).
Ahmadi, M., Emery, D. C. & Morgan, D. J. Prevention of both direct and cross-priming of antitumor CD8+ T-cell responses following overproduction of prostaglandin E2 by tumor cells in vivo. Cancer Res. 68, 7520–7529 (2008).
Doitsh, G. et al. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 143, 789–801 (2010).
Monroe, K. M. et al. IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV. Science 343, 428–432 (2014).
Linder, A. et al. CARD8 inflammasome activation triggers pyroptosis in human T cells. EMBO J. 39, e105071 (2020).
Johnson, D. C. et al. DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes. Cell Death Dis. 11, 628 (2020).
Li, W. et al. Activation of NLRC4 downregulates TLR5-mediated antibody immune responses against flagellin. Cell Mol. Immunol. 13, 514–523 (2016).
Alhallaf, R. et al. The NLRP3 inflammasome suppresses protective immunity to gastrointestinal helminth infection. Cell Rep. 23, 1085–1098 (2018).
Suschak, J. J., Wang, S., Fitzgerald, K. A. & Lu, S. Identification of Aim2 as a sensor for DNA vaccines. J. Immunol. 194, 630–636 (2015).
Seydoux, E. et al. Effective combination adjuvants engage both TLR and inflammasome pathways to promote potent adaptive immune responses. J. Immunol. 201, 98–112 (2018).
Smedberg, J. R., Westcott, M. M., Ahmed, M. & Lyles, D. S. Signaling pathways in murine dendritic cells that regulate the response to vesicular stomatitis virus vectors that express flagellin. J. Virol. 88, 777–785 (2014).
Eisenbarth, S. C., Colegio, O. R., O’Connor, W., Sutterwala, F. S. & Flavell, R. A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453, 1122–1126 (2008).
Li, H., Willingham, S. B., Ting, J. P. & Re, F. Cutting edge: inflammasome activation by alum and alum’s adjuvant effect are mediated by NLRP3. J. Immunol. 181, 17–21 (2008).
Wen, Y. & Shi, Y. Alum: an old dog with new tricks. Emerg. Microbes Infect. 5, e25 (2016).
Franchi, L. & Núñez, G. The Nlrp3 inflammasome is critical for aluminium hydroxide-mediated IL-1β secretion but dispensable for adjuvant activity. Eur. J. Immunol. 38, 2085–2089 (2008).
McKee, A. S. et al. 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 (2009).
Chang, M.-K. et al. Apoptotic cells with oxidation-specific epitopes are immunogenic and proinflammatory. J. Exp. Med. 200, 1359–1370 (2004).
Imai, Y. et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell 133, 235–249 (2008).
Zanoni, I. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science 352, 1232–1236 (2016).
Zhivaki, D. et al. Inflammasomes within hyperactive murine dendritic cells stimulate long-lived T cell-mediated anti-tumor immunity. Cell Rep. 33, 108381 (2020). This study shows that DCs hyperactived by inflammasome activation can induce an antigen-specific CTL response that is protective against tumors.
Chu, L. H. et al. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat. Commun. 9, 996 (2018).
Muri, J. et al. Cyclopentenone prostaglandins and structurally related oxidized lipid species instigate and share distinct pro- and anti-inflammatory pathways. Cell Rep. 30, 4399–4417.e7 (2020).
Cui, B. et al. Flagellin as a vaccine adjuvant. Expert Rev. Vaccines 17, 335–349 (2018).
Ahmed, M. et al. Stimulation of human dendritic cells by wild-type and M protein mutant vesicular stomatitis viruses engineered to express bacterial flagellin. J. Virol. 84, 12093–12098 (2010).
Garaude, J., Kent, A., van Rooijen, N. & Blander, J. M. Simultaneous targeting of Toll- and Nod-like receptors induces effective tumor-specific immune responses. Sci. Transl. Med. 4, 120ra16 (2012).
Nyström, S. et al. DNA-encoded flagellin activates Toll-like receptor 5 (TLR5), Nod-like receptor family CARD domain-containing protein 4 (NRLC4), and acts as an epidermal, systemic, and mucosal-adjuvant. Vaccines (Basel) 1, 415–443 (2013).
Tran, H. Q., Ley, R. E., Gewirtz, A. T. & Chassaing, B. Flagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases. Nat. Commun. 10, 5650 (2019).
Vijay-Kumar, M., Carvalho, F. A., Aitken, J. D., Fifadara, N. H. & Gewirtz, A. T. TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin. Eur. J. Immunol. 40, 3528–3534 (2010).
Knudsen, M. L. et al. The adjuvant activity of alphavirus replicons is enhanced by incorporating the microbial molecule flagellin into the replicon. PLoS ONE 8, e65964 (2013).
Sanos, S. L. et al. NLRC4 inflammasome-driven immunogenicity of a recombinant MVA mucosal vaccine encoding flagellin. Front. Immunol. 8, 1988 (2018).
Ko, E.-J. et al. Flagellin-expressing virus-like particles exhibit adjuvant effects on promoting IgG isotype-switched long-lasting antibody induction and protection of influenza vaccines in CD4-deficient mice. Vaccine 37, 3426–3434 (2019).
Zhong, F. L. et al. Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation. Cell 167, 187–202.e17 (2016).
Dupaul-Chicoine, J. et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 43, 751–763 (2015).
Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009). This study is one of the first to identify a critical role for NLRP3-dependent IL-1β in priming antitumor CD8+ T cell immunity.
Ben-Sasson, S. Z. et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J. Exp. Med. 210, 491–502 (2013).
Ben-Sasson, S. Z., Wang, K., Cohen, J. & Paul, W. E. IL-1β strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb. Symp. Quant. Biol. 78, 117–124 (2013).
Lin, K.-H. et al. Carboxyl-terminal fusion of E7 into flagellin shifts TLR5 activation to NLRC4/NAIP5 activation and induces TLR5-independent anti-tumor immunity. Sci. Rep. 6, 24199 (2016).
Lee, P.-H. et al. Host conditioning with IL-1β improves the antitumor function of adoptively transferred T cells. J. Exp. Med. 216, 2619–2634 (2019).
Segovia, M. et al. Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation. Cancer Cell 35, 767–781.e6 (2019).
Zhou, T. et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature 583, 609–614 (2020).
Das, S., Shapiro, B., Vucic, E. A., Vogt, S. & Bar-Sagi, D. Tumor cell-derived IL1β promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res. 80, 1088–1101 (2020).
Daley, D. et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J. Exp. Med. 214, 1711–1724 (2017).
Theivanthiran, B. et al. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J. Clin. Invest. 130, 2570–2586 (2020).
van Deventer, H. W. et al. The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res. 70, 10161–10169 (2010).
Xia, X. et al. The role of pyroptosis in cancer: pro-cancer or pro-‘‘host’’? Cell Death Dis. 10, 650 (2019).
Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).
Wang, Q. et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature 579, 421–426 (2020). This study used a conjugate of gasdermin-A3 and a gold nanoparticle to selectively induce pyroptosis in tumor cells. These pyroptotic tumor cells induced a strong antitumor response that was dependent on CD4+ and CD8+ T cells.
Xi, G. et al. GSDMD is required for effector CD8+ T cell responses to lung cancer cells. Int. Immunopharmacol. 74, 105713 (2019).
Zhang, Z. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579, 415–420 (2020). This study shows that granzyme B released into tumor cells from CTLs and NK cells can cleave and activate gasdermin-E to kill the cells through pyroptosis. The authors hypothesize that this inflammatory cell death acts as a feed-forward mechanism to recruit more immune cells into the tumor environment.
Zhou, Z. et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science 368, eaaz7548 (2020). This study shows that granzyme A released into tumor cells from CTLs and NK cells can induce pyroptosis through the cleavage of gasdermin-B. It further confirmed gasdermin-B expression in clinical samples of colon, rectal, pancreatic, cervical, gastric and esophageal cancers.
Harapas, C. R., Steiner, A., Davidson, S. & Masters, S. L. An update on autoinflammatory diseases: inflammasomopathies. Curr. Rheumatol. Rep. 20, 40 (2018).
Meng, G., Zhang, F., Fuss, I., Kitani, A. & Strober, W. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity 30, 860–874 (2009).
Brydges, S. D. et al. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30, 875–887 (2009).
Nichols, R. D., von Moltke, J. & Vance, R. E. NAIP/NLRC4 inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease. Nat. Commun. 8, 2209 (2017).
Tartey, S. & Kanneganti, T.-D. Inflammasomes in the pathophysiology of autoinflammatory syndromes. J. Leukoc. Biol. 107, 379–391 (2020).
Inoue, M., Williams, K. L., Gunn, M. D. & Shinohara, M. L. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109, 10480–10485 (2012).
Gris, D. et al. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J. Immunol. 185, 974–981 (2010).
Barclay, W. & Shinohara, M. L. Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Brain Pathol. 27, 213–219 (2017).
Martin, B. N. et al. T cell–intrinsic ASC critically promotes TH17-mediated experimental autoimmune encephalomyelitis. Nat. Immunol. 17, 583–592 (2016).
Braga, T. T. et al. NLRP3 gain-of-function in CD4+ T lymphocytes ameliorates experimental autoimmune encephalomyelitis. Clin. Sci. (Lond.) 133, 1901–1916 (2019).
Reboldi, A. et al. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345, 679–684 (2014).
Li, S. et al. Gasdermin D in peripheral myeloid cells drives neuroinflammation in experimental autoimmune encephalomyelitis. J. Exp. Med. 216, 2562–2581 (2019).
Liu, H. et al. Downregulated NLRP3 and NLRP1 inflammasomes signaling pathways in the development and progression of type 1 diabetes mellitus. Biomed. Pharmacother. 94, 619–626 (2017).
Motta, V. N. et al. Identification of the inflammasome Nlrp1b as the candidate gene conferring diabetes risk at the Idd4.1 locus in the nonobese diabetic mouse. J. Immunol. 194, 5663–5673 (2015).
Carlos, D. et al. Mitochondrial DNA activates the NLRP3 inflammasome and predisposes to type 1 diabetes in murine model. Front. Immunol. 8, 164 (2017).
Hu, C. et al. NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets. Proc. Natl Acad. Sci. USA 112, 11318–11323 (2015). Following up on a study that linked two single-nucleotide polymorphisms in the Nlrp3 gene with a predisposition for type 1 diabetes, this study was the first to show that NLRP3 expression in both hematopoietic and non-hematopoietic cells significantly contributes to the immune cell migration into pancreatic islets.
Lebreton, F. et al. NLRP3 inflammasome is expressed and regulated in human islets. Cell Death Dis. 9, 726 (2018).
Qiu, C. C., Caricchio, R. & Gallucci, S. Triggers of autoimmunity: the role of bacterial infections in the extracellular exposure of lupus nuclear autoantigens. Front. Immunol. 10, 2608 (2019).
Shin, M. S. et al. Self double-stranded (ds)DNA induces IL-1β production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies. J. Immunol. 190, 1407–1415 (2013).
Lu, A. et al. Hyperactivation of the NLRP3 inflammasome in myeloid cells leads to severe organ damage in experimental lupus. J. Immunol. 198, 1119–1129 (2017).
Zhao, J. et al. P2X7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis Rheum. 65, 3176–3185 (2013).
Choy, M. C., Visvanathan, K. & De Cruz, P. An overview of the innate and adaptive immune system in inflammatory bowel disease. Inflamm. Bowel Dis. 23, 2–13 (2017).
Tye, H. et al. NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease. Nat. Commun. 9, 3728 (2018).
Yao, X. et al. Remodelling of the gut microbiota by hyperactive NLRP3 induces regulatory T cells to maintain homeostasis. Nat. Commun. 8, 1896 (2017).
Gong, Z. et al. Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammasome activation and IL-1β production. Mol. Immunol. 104, 11–19 (2018).
Mak’Anyengo, R. et al. Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut. JCI Insight 3, e96322 (2018).
Holmkvist, P., Pool, L., Hagerbrand, K., Agace, W. W. & Rivollier, A. IL-18Rα-deficient CD4+ T cells induce intestinal inflammation in the CD45RBhi transfer model of colitis despite impaired innate responsiveness. Eur. J. Immunol. 46, 1371–1382 (2016).
Guan, Q. et al. Sustained suppression of IL-18 by employing a vaccine ameliorates intestinal inflammation in TNBS-induced murine colitis. Future Sci. OA 5, FSO405 (2019).
Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug Discov. 17, 588–606 (2018).
Xu, S. et al. Inflammasome inhibitors: promising therapeutic approaches against cancer. J. Hematol. Oncol. 12, 64 (2019).
Christgen, S., Place, D. E. & Kanneganti, T.-D. Toward targeting inflammasomes: insights into their regulation and activation. Cell Res. 30, 315–327 (2020).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002).
Research in R.E.V.’s lab is supported by an Investigator Award from the Howard Hughes Medical Institute and by National Institutes of Health grant nos. AI063302, AI075039 and AI155634. Additionally, the authors thank M. Gaidt, I. Rauch and D. Kotov for providing invaluable scientific insights and editorial feedback.
R.E.V. is a consultant for Ventus Therapeutics.
Peer review information L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Deets, K.A., Vance, R.E. Inflammasomes and adaptive immune responses. Nat Immunol (2021). https://doi.org/10.1038/s41590-021-00869-6