STAT1 signaling shields T cells from NK cell-mediated cytotoxicity

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Colitis / pathology*
  • Histocompatibility Antigens Class I / immunology
  • Intestines / immunology
  • Intestines / pathology*
  • Intracellular Signaling Peptides and Proteins / biosynthesis
  • Killer Cells, Natural / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • STAT1 Transcription Factor / genetics*
  • STAT1 Transcription Factor / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology


  • Histocompatibility Antigens Class I
  • Intracellular Signaling Peptides and Proteins
  • NLRC5 protein, mouse
  • STAT1 Transcription Factor
  • Stat1 protein, mouse