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A STAT3-dependent transcriptional circuitry inhibits cytotoxic gene expression in T cells

  1. Rémy Bosseluta,1
  1. aLaboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
  1. Edited by Christophe Benoist, Harvard Medical School, Boston, MA, and approved October 26, 2017 (received for review June 20, 2017)

Significance

The acquisition of cytotoxic function by CD8+ T cells is critical for antiviral and antitumor responses. While cytotoxic differentiation is preprogrammed during CD8+ T-cell development in the thymus, the regulation of T-cell cytotoxic capacities by inflammatory cues is poorly understood, notably in cases of immune dysfunction observed in tumor-infiltrating lymphocytes or during chronic infections. Here, we demonstrate that the program underlying IL-17 production dampens cytotoxic function in both CD4+ and CD8+ T cells. Specifically, we show that two transcription factors involved in IL-17 production, STAT3 and RORγt, repress cytotoxic differentiation. These results highlight the role of the inflammatory environment on T-cell responses and have implications for the development of T cell-based immunotherapies.

Abstract

CD8+ T cells are preprogrammed for cytotoxic differentiation in the thymus as they acquire expression of the transcription factor Runx3. However, a subset of effector CD8+ T cells (Tc17) produce IL-17 and fail to express cytotoxic genes. Here, we show that the transcription factors directing IL-17 production, STAT3 and RORγt, inhibit cytotoxicity despite persistent Runx3 expression. Cytotoxic gene repression did not require the transcription factor Thpok, which in CD4+ T cells restrains Runx3 functions and cytotoxicity; and STAT3 restrained cytotoxic gene expression in CD8+ T cells responding to viral infection in vivo. STAT3-induced RORγt represses cytotoxic genes by inhibiting the functions but not the expression of the “cytotoxic” transcription factors T-bet and Eomesodermin. Thus, the transcriptional circuitry directing IL-17 expression inhibits cytotoxic functions. However, by allowing expression of activators of the cytotoxic program, this inhibitory mechanism contributes to the instability of IL-17–producing T cells.

Footnotes

  • ?1To whom correspondence should be addressed. Email: remy{at}helix.nih.gov.

Published under the PNAS license.

Online Impact

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