STAT1 signaling shields T cells from NK cell-mediated cytotoxicity

Nature Communications
Yu Hui KangScott B Snapper

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.

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Citations

Jan 19, 2021·Artificial Cells, Nanomedicine, and Biotechnology·Chengquan ShenYonghua Wang
Apr 4, 2021·International Journal of Molecular Sciences·Ryuhjin Ahn, Josie Ursini-Siegel
Apr 5, 2021·Cellular and Molecular Gastroenterology and Hepatology·Roman KosoyMayte Suárez-Fariñas
Jul 1, 2021·Journal of breast cancer·Sayantan BanikKoustav Sarkar

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Datasets Mentioned

BETA
GSE116475

Methods Mentioned

BETA
flow
flow cytometry
RNA-seq
Fluorescence
PMA

Software Mentioned

DESeq2
STAR
GraphPad Prism
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