CD44 expression on murine hepatic stellate cells promotes the induction of monocytic and polymorphonuclear myeloid-derived suppressor cells.

Abstract

In chronic inflammation regulatory immune cells, such as regulatory T cells and myeloid-derived suppressor cells (MDCS) can develop. Local signals in the inflamed tissue, such as cytokines and eicosanoids, but also contact dependent signals, can promote MDSC development. In the liver, hepatic stellate cells (HSC) may provide such signals via the expression of CD44. MDSC generated in the presence of HSC and anti-CD44 antibodies were functionally and phenotypically analyzed. We found that both monocytic (M-) and polymorphonuclear (PMN-) MDSC generated in the presence of αCD44 antibodies were less suppressive towards T cells as measured by T cell proliferation and cytokine production. Moreover, both M- and PMN- MDSC were phenotypically altered. M-MDSC mainly changed their expression of CD80 and CD39, PMN-MDSC showed altered expression of CD80/86, PD-L1 and CCR2. Moreover, both PMN- and M-MDSC lost expression of Nos2 mRNA, whereas M-MDSC showed reduced expression of TGFb mRNA and PMN-MDSC reduced expression of Il10 mRNA. In summary, the presence of CD44 on hepatic stellate cells promotes the induction of both M- and PMN-MDSC, although the mechanisms by which these MDSC may increase suppressive function due to interaction with CD44 is only partially overlapping.