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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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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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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DOI: https://doi.org/10.1038/ni.2195
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