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TH17 cell heterogeneity and its role in tissue inflammation

Abstract

Since their discovery almost two decades ago, interleukin-17-producing CD4+ T cells (TH17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, TH17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has led to substantial progress in the understanding of TH17 cell heterogeneity in tissues and of TH17 cell plasticity leading to alternative T cell states and differing functions. In this Review, we discuss the heterogeneity of TH17 cells and the role of this heterogeneity in diverse functions of TH17 cells from homeostasis to tissue inflammation. In addition, we discuss TH17 cell plasticity and its incorporation into the current understanding of T cell subsets and alternative views on the role of TH17 cells in autoimmune and inflammatory diseases.

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Fig. 1: TH17 cell heterogeneity in intestinal homeostasis.
Fig. 2: Drivers of tissue-specific signatures of immune cells.
Fig. 3: TH1 and TH17 cell subsets in tolerance and inflammation.
Fig. 4: TH17 cells in intestinal and extraintestinal autoimmunity.

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Acknowledgements

We thank M. Collins for critical feedback on the manuscript. We thank laboratory members of the D.R.L. and V.K.K. laboratories for contributions to some of the discussed studies. This work was supported by National Institutes of Health grants R01NS045937, R01NS30843, R01AI144166, P01AI073748, P01AI039671 and P01AI056299 (to V.K.K.) and R01AI158687 and RO1CA255635 (to D.R.L.). A.S. was supported by a German Academic Scholarship Foundation (Studienstiftung des Deutschen Volkes) PhD fellowship.

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Correspondence to Dan R. Littman or Vijay K. Kuchroo.

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V.K.K. is cofounder of Celsius Therapeutics, Tizona Therapeutics, Larkspur Biosciences and Bicara Therapeutics. His interests are reviewed and managed by the Brigham and Women’s Hospital and Partners Health Care in accordance with their conflict of interest policies. D.R.L. is cofounder of Vedanta Biosciences and Immunai, on the advisory boards of ChemoCentryx and IMIDomics and on the board of directors of Pfizer. The other authors declare no competing interests.

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Schnell, A., Littman, D.R. & Kuchroo, V.K. TH17 cell heterogeneity and its role in tissue inflammation. Nat Immunol 24, 19–29 (2023). https://doi.org/10.1038/s41590-022-01387-9

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