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=8 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 (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.