Article | Published:

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

Nature Immunology volume 14, pages 136142 (2013) | Download Citation

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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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.

Author information

Affiliations

  1. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Megan Raetz
    • , Sun-hee Hwang
    • , Cara L Wilhelm
    • , Donna Kirkland
    • , Alicia Benson
    • , Carolyn R Sturge
    • , Julie Mirpuri
    • , Shipra Vaishnava
    • , Lora V Hooper
    •  & Felix Yarovinsky
  2. Department of Microbiology & Immunology, University of California, San Francisco, California, USA.

    • Baidong Hou
    •  & Anthony L DeFranco
  3. Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

    • Baidong Hou
  4. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Christopher J Gilpin
  5. The Howard Hughes Medical Institute.

    • Lora V Hooper

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Contributions

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Felix Yarovinsky.

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DOI

https://doi.org/10.1038/ni.2508

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