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  • Review Article
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The development and in vivo function of T helper 9 cells

Key Points

  • Although interleukin-9 (IL-9) is produced by several types of immune cells, IL-9-secreting T helper 9 (TH9) cells are a predominant source of IL-9 in T cell-dependent allergic inflammation and antiparasite immunity.

  • TH9 cell differentiation is initiated by IL-4–signal transducer and activator of transcription 6 (STAT6), IL-2–STAT5 and transforming growth factor-β (TGFβ)-mediated signalling pathways.

  • STAT6 is responsible for the expression of the majority of TH9 cell-associated genes (including the genes encoding the key transcription factors interferon-regulatory factor 4 (IRF4) and basic leucine zipper transcription factor ATF-like (BATF)). By contrast, TGFβ signalling, through both SMAD-dependent and PU.1-dependent pathways, is responsible for the induction of only a few TH9 cell-associated genes. Despite this apparent imbalance, both of these pathways are equally required for optimal TH9 cell differentiation.

  • Although TH9 cells are fairly unstable in vitro using our current culturing methods, IL-9-producing CD4+ T cells are readily identified in vivo. These cells rely on IL-9-dependent effector function and have a role in the induction and the pathogenesis of atopic disease, antiparasite immunity and immunopathological diseases of the gut.

  • The tissue-tropism of human TH9 cells includes localization to the skin and the gut.

  • TH9 cells produce other lineage-associated cytokines (such as IL-3 and IL-21) that promote antitumour immunity and that possibly contribute to additional aspects of inflammatory disease.

Abstract

The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the twentieth anniversary of the first descriptions of the cytokine signals that promote the differentiation of interleukin-9 (IL-9)-secreting T cells, this Review focuses on the extracellular signals and the transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease, and we propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.

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Figure 1: Influence of the cytokine environment on TH cell differentiation.
Figure 2: Cytokine and signal transduction pathways that promote interleukin-9 production and TH9 cell differentiation.
Figure 3: TH9 cells in immunity and disease.

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Acknowledgements

Work in the Kaplan laboratory and preparation of this Review was supported by Public Health Service grant AI057459 to M.H.K. M.M.H. and M.R.O. were supported by Public Health Service T32 Training grants AI060519 and AR062495, respectively.

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Kaplan, M., Hufford, M. & Olson, M. The development and in vivo function of T helper 9 cells. Nat Rev Immunol 15, 295–307 (2015). https://doi.org/10.1038/nri3824

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