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Nat Commun. 2019 Feb 22;10(1):912. doi: 10.1038/s41467-019-08743-8.

STAT1 signaling shields T cells from NK cell-mediated cytotoxicity.

Author information

1
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, 02115, USA.
2
Harvard Medical School, Boston, MA, 02115, USA.
3
Discovery Immunology, Abbvie, 200 Sidney Street, Cambridge, MA, 02139, USA.
4
Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, 02115, USA. Scott.Snapper@childrens.harvard.edu.
5
Harvard Medical School, Boston, MA, 02115, USA. Scott.Snapper@childrens.harvard.edu.

Abstract

The JAK-STAT pathway critically regulates T-cell differentiation, and STAT1 is postulated to regulate several immune-mediated diseases by inducing proinflammatory subsets. Here we show that STAT1 enables CD4+ T-cell-mediated intestinal inflammation by protecting them from natural killer (NK) cell-mediated elimination. Stat1-/- T cells fail to expand and establish colitis in lymphopenic mice. This defect is not fully recapitulated by the combinatorial loss of type I and II IFN signaling. Mechanistically, Stat1-/- T cells have reduced expression of Nlrc5 and multiple MHC class I molecules that serve to protect cells from NK cell-mediated killing. Consequently, the depletion of NK cells significantly rescues the survival and spontaneous proliferation of Stat1-/- T cells, and restores their ability to induce colitis in adoptive transfer mouse models. Stat1-/- mice however have normal CD4+ T cell numbers as innate STAT1 signaling is required for their elimination. Overall, our findings reveal a critical perspective on JAK-STAT1 signaling that might apply to multiple inflammatory diseases.

PMID:
30796216
PMCID:
PMC6385318
DOI:
10.1038/s41467-019-08743-8
[Indexed for MEDLINE]
Free PMC Article

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