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Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13236-13241. doi: 10.1073/pnas.1711160114. Epub 2017 Nov 27.

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

Author information

1
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
2
Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 remy@helix.nih.gov.

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.

KEYWORDS:

CD8 T cells; IL-17; STAT3 signaling; cytotoxicity

PMID:
29180433
PMCID:
PMC5740647
DOI:
10.1073/pnas.1711160114
[Indexed for MEDLINE]
Free PMC Article

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