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

TITLE=IFN-γ–STAT1–iNOS Induces Myeloid Progenitors to Acquire Immunosuppressive Activity

JOURNAL=Frontiers in Immunology

VOLUME=Volume 8 - 2017

YEAR=2017

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01192

DOI=10.3389/fimmu.2017.01192

ISSN=1664-3224

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, which were myeloid progenitors (Lineage-Sca-1-c-Kit+) that upregulated Sca-1 expression upon T cell derived IFN-γ stimulation. Strikingly, bone marrow 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.