SSChighCD11bhighLy-6ChighLy-6Glow myeloid cells curtail CD4 T cell response by inducible nitric oxide synthase in murine hepatitis

Abstract

Myeloid-derived suppressor cells (MDSCs) play an important role in maintaining immune tolerance in response to tumors and inflammatory diseases. Several liver MDSCs have been described in hepatitis in humans and mouse models. Although all the murine MDSCs are CD11b+Gr-1+, their true phenotype and mechanism of suppression remain elusive. This study revealed that SSChighCD11bhighLy-6ChighLy-6Glow monocytic cells but not the other liver-infiltrating, CD11b+Gr-1+ subsets could suppress CD4 T cell responses. Their suppressive activity was remarkably effective even at a ratio of 1:50 when co-cultured with CD4 T cells. Mechanistically, the suppression was dependent on nitric oxide production by inducible nitric oxide synthase (iNOS). Furthermore, the suppressive function by these liver MDSCs was found to require direct contact with activated CD4 T cells. Adoptive transfer experiments demonstrate that these liver MDSCs can dramatically ameliorate concanavalin A (Con A)-induced fulminant hepatitis in mice. Finally, MDSC-mediated suppression in vivo was dependent on iNOS expression. Altogether, SSChighCD11bhighLy-6ChighLy-6Glow cells represent authentic MDSCs in the inflammatory liver and may function to minimize collateral damage caused by an overzealous CD4 T cell response following hepatitis infection.