Nonparenchymal cells appear to be critical to maintain the immunoprivileged status of liver as whole liver allografts are well-tolerated in mice, but allo-hepatocytes are rapidly rejected. Hepatic stellate cells (HSCs), which account for one third of the Nonparenchymal cells in the liver, potently inhibit T cells, a process that could help the liver to maintain its immunoprivileged status. HSCs secrete latent TGFβ1, but the detailed mechanisms by which latent TGFβ1 is activated and whether it plays any role in HSC-mediated T-cell suppression remain unclear. Glycoprotein A repetitions predominant (GARP) is a surface marker of activated regulatory T cells (Tregs). GARP binds latent TGFβ1 for its activation, which is critical for Tregs to suppress effector T cells; however, it remains unclear whether GARP is present on HSCs and whether it has any impact on HSC function. In this study, we discovered that TGFβ1^+/ HSCs, which produce reduced levels of TGFβ1, showed decreased potency in inhibiting T cells. Pharmaceutical inhibition of the TGFβ1 signaling pathway reduced the T-cell-inhibiting activity of HSCs. SMAD3 ^/ T cells with genetically impaired TGFβ1 signaling were resistant to HSC-mediated suppression. We demonstrated that GARP was constitutively expressed on primary HSCs isolated from normal mouse. Blocking GARP function with antibodies or knocking down GARP expression using shRNAs significantly impaired the potency of HSCs to suppress T cell proliferative response and IFNγ production, suggesting that GARP is important for HSCs to inhibit T cells. These results demonstrate the presence of GARP on HSCs and its critical role in regard to the ability of HSCs to activate latent TGFβ1 and thereby inhibit T cells. Our study reveals a novel mechanism for HSC-mediated immune regulation and potentially for other conditions, such as liver fibrosis, that involve HSC-secreted TGFβ1.

Supported in part by grants MDA234458 (FL) and DK84192(LL)

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