IFN-γ-STAT1-iNOS induces myeloid progenitors to acquire immunosuppressive activity

Shu Han Yang, Liang Li, Yu Qing Xie, Yuan Yao, Cai Yue Gao, Liang Huan Liao, Hong Di Ma, M. Eric Gershwin, Zhe Xiong Lian

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Autoimmune diseases often induce dysregulated hematopoiesis with altered number and function of hematopoietic stem and progenitor cells (HSPCs). However, there are limited studies on the direct regulation of HSPCs on T cells, which are often detrimental to autoimmunity. Here, we found that in a murine model of Concanavalin A-induced autoimmune hepatitis, LSK (Lineage-Sca-1+c-Kit+)-like cells accumulated in liver, spleen, and bone marrow (BM), which were myeloid progenitors (Lineage-Sca-1-c-Kit+) that upregulated Sca-1 expression upon T cell-derived IFN-γ stimulation. Strikingly, BM LSK-like cells from mice induced by Con A to develop autoimmune hepatitis or alternatively myeloid progenitors from wild-type mice possessed strong in vitro suppressive ability. Their suppressive function depended on T cell-derived IFN-γ in a paracrine fashion, which induced STAT1 phosphorylation, inducible nitric oxide synthase expression, and nitric oxide production. Blocking IFN-γ/IFN-γ receptor interaction, knockout of STAT1, or iNOS inhibition abrogated their suppressive function. In addition, the suppressive function was independent of differentiation; mitomycin C-treated myeloid progenitors maintained T cell suppressive ability in vitro. Our data demonstrate a mechanism of inflammation induced suppressive function of myeloid progenitors, which may participate directly in suppressing T cell-mediated immunopathology.

Original languageEnglish (US)
Article number1192
JournalFrontiers in Immunology
Volume8
Issue numberSEP
DOIs
StatePublished - Sep 22 2017

Keywords

  • Autoimmune disease
  • Bone marrow
  • IFN-γ
  • Immunosuppression
  • Inducible nitride oxide synthase
  • Myeloid progenitors
  • STAT1
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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