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NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells

Abstract

Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8+ T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α+ DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1β, only IL-18 was required for IFN-γ production by memory CD8+ T cells. Conversely, only the release of IL-1β, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.

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Figure 1: Noncognate memory CD8+ T cells secrete IFN-γ in response to S. Typhimurium and contribute to the control of S. Typhimurium infections.
Figure 2: Bacterial flagellin is required for S. Typhimurium–induced IFN-γ secretion by memory T cells.
Figure 3: T cell–intrinsic IL-18R-MyD88 signaling and NLRC4 inflammasomes are required for IFN-γ production by memory CD8+ T cells.
Figure 4: NLRC4 inflammasomes are required for IFN-γ secretion and IL-18 release in response to S. Typhimurium, Y. pseudotuberculosis and P. aeruginosa.
Figure 5: DCs provide IL-18 in response to inflammasome activation.
Figure 6: Release of IL-1β, but not of IL-18, depends on TLR stimulation.

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References

  1. Williams, M.A. & Bevan, M.J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).

    Article  CAS  Google Scholar 

  2. Berg, R.E., Crossley, E., Murray, S. & Forman, J. Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen. J. Exp. Med. 198, 1583–1593 (2003).

    Article  CAS  Google Scholar 

  3. Tough, D.F., Sun, S. & Sprent, J. T cell stimulation in vivo by lipopolysaccharide (LPS). J. Exp. Med. 185, 2089–2094 (1997).

    Article  CAS  Google Scholar 

  4. Kohlmeier, J.E., Cookenham, T., Roberts, A.D., Miller, S.C. & Woodland, D.L. Type I interferons regulate cytolytic activity of memory CD8(+) T cells in the lung airways during respiratory virus challenge. Immunity 33, 96–105 (2010).

    Article  CAS  Google Scholar 

  5. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  Google Scholar 

  6. Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

    Article  CAS  Google Scholar 

  7. Franchi, L., Eigenbrod, T., Munoz-Planillo, R. & Nunez, G. The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat. Immunol. 10, 241–247 (2009).

    Article  CAS  Google Scholar 

  8. Manicassamy, S. & Pulendran, B. Modulation of adaptive immunity with Toll-like receptors. Semin. Immunol. 21, 185–193 (2009).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. Shortman, K. & Heath, W.R. The CD8+ dendritic cell subset. Immunol. Rev. 234, 18–31 (2010).

    Article  CAS  Google Scholar 

  11. Shortman, K. & Naik, S.H. Steady-state and inflammatory dendritic-cell development. Nat. Rev. Immunol. 7, 19–30 (2007).

    Article  CAS  Google Scholar 

  12. Heath, W.R. & Carbone, F.R. Dendritic cell subsets in primary and secondary T cell responses at body surfaces. Nat. Immunol. 10, 1237–1244 (2009).

    Article  CAS  Google Scholar 

  13. Sander, L.E. et al. Detection of prokaryotic mRNA signifies microbial viability and promotes immunity. Nature 474, 385–389 (2011).

    Article  CAS  Google Scholar 

  14. Netea, M.G. et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1β in monocytes and macrophages. Blood 113, 2324–2335 (2009).

    Article  CAS  Google Scholar 

  15. Piccini, A. et al. ATP is released by monocytes stimulated with pathogen-sensing receptor ligands and induces IL-1β and IL-18 secretion in an autocrine way. Proc. Natl. Acad. Sci. USA 105, 8067–8072 (2008).

    Article  CAS  Google Scholar 

  16. Jouanguy, E. et al. IL-12 and IFN-γ in host defense against mycobacteria and Salmonella in mice and men. Curr. Opin. Immunol. 11, 346–351 (1999).

    Article  CAS  Google Scholar 

  17. VanCott, J.L. et al. Regulation of host immune responses by modification of Salmonella virulence genes. Nat. Med. 4, 1247–1252 (1998).

    Article  CAS  Google Scholar 

  18. Waithman, J., Gebhardt, T., Davey, G.M., Heath, W.R. & Carbone, F.R. Cutting edge: enhanced IL-2 signaling can convert self-specific T cell response from tolerance to autoimmunity. J. Immunol. 180, 5789–5793 (2008).

    Article  CAS  Google Scholar 

  19. Tough, D.F., Borrow, P. & Sprent, J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 272, 1947–1950 (1996).

    Article  CAS  Google Scholar 

  20. Khan, S.A. et al. A lethal role for lipid A in Salmonella infections. Mol. Microbiol. 29, 571–579 (1998).

    Article  CAS  Google Scholar 

  21. Miao, E.A. et al. Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf. Nat. Immunol. 7, 569–575 (2006).

    Article  CAS  Google Scholar 

  22. Salazar-Gonzalez, R.M. & McSorley, S.J. Salmonella flagellin, a microbial target of the innate and adaptive immune system. Immunol. Lett. 101, 117–122 (2005).

    Article  CAS  Google Scholar 

  23. Haraga, A., Ohlson, M.B. & Miller, S.I. Salmonellae interplay with host cells. Nat. Rev. Microbiol. 6, 53–66 (2008).

    Article  CAS  Google Scholar 

  24. Kambayashi, T., Assarsson, E., Lukacher, A.E., Ljunggren, H.G. & Jensen, P.E. Memory CD8+ T cells provide an early source of IFN-γ. J. Immunol. 170, 2399–2408 (2003).

    Article  CAS  Google Scholar 

  25. Raué, H.P., Brien, J.D., Hammarlund, E. & Slifka, M.K. Activation of virus-specific CD8+ T cells by lipopolysaccharide-induced IL-12 and IL-18. J. Immunol. 173, 6873–6881 (2004).

    Article  Google Scholar 

  26. Arend, W.P., Palmer, G. & Gabay, C. IL-1, IL-18, and IL-33 families of cytokines. Immunol. Rev. 223, 20–38 (2008).

    Article  CAS  Google Scholar 

  27. Kofoed, E.M. & Vance, R.E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592–595 (2011).

    Article  CAS  Google Scholar 

  28. Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011).

    Article  CAS  Google Scholar 

  29. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    Article  CAS  Google Scholar 

  30. Smith, K.D. et al. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat. Immunol. 4, 1247–1253 (2003).

    Article  CAS  Google Scholar 

  31. Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).

    Article  CAS  Google Scholar 

  32. Osuka, A., Hanschen, M., Stoecklein, V. & Lederer, J.A. A protective role for inflammasome activation following injury. Shock 37, 47–55 (2011).

    Article  Google Scholar 

  33. Lin, M.L. et al. Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset. Proc. Natl. Acad. Sci. USA 105, 3029–3034 (2008).

    Article  CAS  Google Scholar 

  34. Latz, E. The inflammasomes: mechanisms of activation and function. Curr. Opin. Immunol. 22, 28–33 (2010).

    Article  CAS  Google Scholar 

  35. Puren, A.J., Fantuzzi, G. & Dinarello, C.A. Gene expression, synthesis, and secretion of interleukin 18 and interleukin 1β are differentially regulated in human blood mononuclear cells and mouse spleen cells. Proc. Natl. Acad. Sci. USA 96, 2256–2261 (1999).

    Article  CAS  Google Scholar 

  36. Mariathasan, S. & Monack, D.M. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat. Rev. Immunol. 7, 31–40 (2007).

    Article  CAS  Google Scholar 

  37. Elinav, E., Strowig, T., Henao-Mejia, J. & Flavell, R.A. Regulation of the antimicrobial response by NLR proteins. Immunity 34, 665–679 (2011).

    Article  CAS  Google Scholar 

  38. Broz, P. et al. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J. Exp. Med. 207, 1745–1755 (2010).

    Article  CAS  Google Scholar 

  39. Miao, E.A. et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 11, 1136–1142 (2010).

    Article  CAS  Google Scholar 

  40. Vazquez-Torres, A., Jones-Carson, J., Mastroeni, P., Ischiropoulos, H. & Fang, F.C. Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro. J. Exp. Med. 192, 227–236 (2000).

    Article  CAS  Google Scholar 

  41. Minnich, S.A. & Rohde, H.N. A rationale for repression and/or loss of motility by pathogenic Yersinia in the mammalian host. Adv. Exp. Med. Biol. 603, 298–310 (2007).

    Article  Google Scholar 

  42. Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nat. Immunol. 7, 576–582 (2006).

    Article  CAS  Google Scholar 

  43. Neuenhahn, M. et al. CD8α+ dendritic cells are required for efficient entry of Listeria monocytogenes into the spleen. Immunity 25, 619–30 (2006).

    Article  CAS  Google Scholar 

  44. Bauernfeind, F.G. et al. Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787–791 (2009).

    Article  CAS  Google Scholar 

  45. Takeda, K. et al. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8, 383–390 (1998).

    Article  CAS  Google Scholar 

  46. Gu, Y. et al. Activation of interferon-γ inducing factor mediated by interleukin-1β converting enzyme. Science 275, 206–209 (1997).

    Article  CAS  Google Scholar 

  47. Yamamoto, M. et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301, 640–643 (2003).

    Article  CAS  Google Scholar 

  48. Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998).

    Article  CAS  Google Scholar 

  49. Davey, G.M. et al. Cutting edge: priming of CD8 T cell immunity to herpes simplex virus type 1 requires cognate TLR3 expression in vivo. J. Immunol. 184, 2243–2246 (2010).

    Article  CAS  Google Scholar 

  50. Bedoui, S. et al. Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat. Immunol. 10, 488–495 (2009).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Maskell (University of Cambridge) for mutant S. Typhimurium strain SL1344 ΔmsbB; R. Robins-Browne (University of Melbourne) for motile E. coli MG1655 and Y. pseudotuberculosis B14; C. Whitchurch (University of Technology, Sydney) for Pseudomonas aeruginosa and P. aeruginosa PAKMS591 (fliC P. aeruginosa); A. Walduck (University of Melbourne) for Helicobacter pylori SS1; F.R. Carbone, E.L. Hartland, A.M. Lew, L. Alexopoulou, S. Akira, R.A. Flavell, D.I. Godfrey and A.G. Brooks for reagents, bacteria, mice and discussions; and A. Turner for assistance. Supported by the National Health and Medical Research Council of Australia (Career Development Awards to T.G., O.L.C.W. and S.B.), the Louis-Jeantet Foundation (G.G. and J.T.) and the Gates Foundation, through the Grand Challenges in Health program (R.C., O.L.C.W. and R.A.S.).

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A.K., R.A.S. and S.B. conceived of the study, designed and undertook experiments and wrote the manuscript; G.G. and J.T. contributed reagents and intellectual input; L.E.S. did immunoblots on splenic DCs; K.R.S., H.C., P.G.W. and R.C. did PCR and generated mutants; J.C.W. and W.C. did experiments and provided reagents; D.A.D. and O.L.C.W. were involved in the initial finding; D.F.-R. generated flt3L DCs and T.G. and W.R.H. provided intellectual input and critically reviewed the manuscript.

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Correspondence to Richard A Strugnell or Sammy Bedoui.

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Kupz, A., Guarda, G., Gebhardt, T. et al. NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells. Nat Immunol 13, 162–169 (2012). https://doi.org/10.1038/ni.2195

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