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Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation

Abstract

Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defence against the invading pathogen. Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified subset, separate from the T helper type 1 (TH1) and T helper type 2 (TH2) subsets1. Synergy between the cytokines transforming growth factor-β and IL-6 in vitro induces development of TH17 cells in mouse1,2,3,4,5 and human6 systems, whereas IL-23 supports expansion of these cells2,4,5. However, it is not known which conditions in vivo would induce this combination of cytokines. Furthermore, it is enigmatic that a combination of pro-inflammatory and anti-inflammatory cytokines would be required to generate an effector TH17 response. Here we show that the relevant physiological stimulus triggering this combination of cytokines is the recognition and phagocytosis of infected apoptotic cells by dendritic cells. Phagocytosis of infected apoptotic cells uniquely triggers the combination of IL-6 and transforming growth factor-β through recognition of pathogen-associated molecular patterns7 and phosphatidylserine exposed on apoptotic cells8, respectively. Conversely, phagocytosis of apoptotic cells in the absence of microbial signals induces differentiation of the closely related regulatory T cells, which are important for controlling autoimmunity9. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium10, which models human infections with the attaching and effacing enteropathogenic and enterohaemorrhagic Escherichia coli, impairs the characteristic TH17 response in the lamina propria. Our results demonstrate that infected apoptotic cells are a critical component of the innate immune signals instructing TH17 differentiation, and point to pathogens particularly adept at triggering apoptosis that might preferentially induce TH17-mediated immunity. Because TH17 cells have been correlated with autoimmune diseases1, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.

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Figure 1: Phagocytosis of infected and TLR-ligand-carrying apoptotic cells induces conditions optimal for development of T H 17 cells.
Figure 2: Development of T H 17 cells in response to infected and TLR-ligand-carrying apoptotic cells requires TGF-β and IL-6 synthesis as well as TLR signalling by DCs.
Figure 3: Development of T H 17 cells in response to infected and TLR-ligand-carrying apoptotic cells is accompanied by production of the immunoregulatory cytokine IL-10.
Figure 4: Blocking apoptosis during C. rodentium infection impairs development of a T H 17 immune response.

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Acknowledgements

We are grateful to R. Medzhitov, L. Mayer and D. Amsen for advice and critical reading of the manuscript, S. Lira for use of cryostat and microscope, B. B. Finlay and W. Deng for Citrobacter mutants, former Blander laboratory members H. Pêche and B. Trinité for technical assistance and discussions, S. Mehrotra for advice with caspase inhibitors, and I. George and M. Grisotto for cell sorting. We are indebted to B. Brown, H. Xiong, G. Frankel, C. Dong, K. Schluns, M. Kamanaka, S. Yu, P. Arnaboldi, M. Bogunovic, B. M. Baker, S. L. Fishman, M. Blander and S. J. Blander for technical advice, assistance and support. J.G. is supported by the Fondation pour la Recherche Médicale, and J.M.B. is supported by NIH grant AI073899 and the Kinship Foundation Searle Scholar Award.

Author Contributions M.B.T. and J.M.B. designed experiments and wrote the manuscript. M.B.T. performed all experiments. J.G. performed RT–qPCRs, bioactive TGF-β assays, and helped with tissue staining. A.P.M. performed tissue sectioning, staining and quantification. J.M.B. initiated and directed the study.

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Correspondence to J. Magarian Blander.

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Torchinsky, M., Garaude, J., Martin, A. et al. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature 458, 78–82 (2009). https://doi.org/10.1038/nature07781

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