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Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells

Abstract

Activation of Toll-like receptors (TLRs) by pathogens triggers cytokine production and T cell activation, immune defense mechanisms that are linked to immunopathology. Here we show that IFN-γ production by CD4+ TH1 cells during mucosal responses to the protozoan parasite Toxoplasma gondii resulted in dysbiosis and the elimination of Paneth cells. Paneth cell death led to loss of antimicrobial peptides and occurred in conjunction with uncontrolled expansion of the Enterobacteriaceae family of Gram-negative bacteria. The expanded intestinal bacteria were required for the parasite-induced intestinal pathology. The investigation of cell type–specific factors regulating TH1 polarization during T. gondii infection identified the T cell–intrinsic TLR pathway as a major regulator of IFN-γ production in CD4+ T cells responsible for Paneth cell death, dysbiosis and intestinal immunopathology.

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Figure 1: T.gondii infection results in intestinal dysbiosis.
Figure 2: T.gondii infection results in loss of Paneth cells.
Figure 3: T.gondii–induced dysbiosis contributes to the intestinal pathology.
Figure 4: TLR11-mediated activation of MyD88 triggers Paneth cell death and intestinal dysbiosis.
Figure 5: IFN-γ mediates loss of Paneth cells.
Figure 6: T cell–intrinsic MyD88 signaling regulates TH1 polarization.
Figure 7: T cell–intrinsic MyD88 signaling mediates loss of Paneth cells intestinal dysbiosis.

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Acknowledgements

This research was supported by US National Institutes of Health (NIH) grants R01 AI085263 to F.Y. and R01 DK070855 to L.V.H. and by the Howard Hughes Medical Institute (L.V.H.). C.R.S. was supported in part by NIH grant A1005284-33. We would also like to thank C. Behrendt and C. Clements for germ-free mouse husbandry.

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F.Y. conceived the project. M.R., S.-h.H., C.L.W., D.K., A.B., C.R.S., J.M., S.V. and C.J.G. performed the experiments. A.L.D. and B.H. provided Myd88fl/fl mice, and L.V.H. provided germ-free mice. M.R., S.-h.H., C.L.W. and F.Y. analyzed data. M.R., C.L.W. and F.Y. wrote the manuscript, with all authors contributing to the writing and providing advice.

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Correspondence to Felix Yarovinsky.

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Raetz, M., Hwang, Sh., Wilhelm, C. et al. Parasite-induced TH1 cells and intestinal dysbiosis cooperate in IFN-γ-dependent elimination of Paneth cells. Nat Immunol 14, 136–142 (2013). https://doi.org/10.1038/ni.2508

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