Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate-responsive element modulator alpha (CREMa) can endorse differentiation of T lymphocytes toward T-helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREMa in liver disease, we subjected transgenic (Tg) mice overexpressing CREMa under control of the CD2 promoter (crem tg mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREMa overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, crem tg mice developed more severe immune-mediated hepatitis with a higher mortality rate, compared to wild-type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREMa overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic crem tg CD4 1 T cells expressed less interleukin (IL)-17 than wt T cells. Reconstitution of Rag1 2/2 mice with Crem 2/2 T cells did not ameliorate ConA hepatitis. Overexpression of CREMa did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid-derived suppressor cells (MDSCs) also expressed CD2 and CREMa. Crem tg MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T-cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune-mediated liver damage in crem tg mice to wt level. Conclusion: These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREMa in hepatic monocytic MDSCs for the pathogenesis of immune-mediated liver disease. (HEPATOLOGY 2015;61:990-1002) A utoimmune hepatitis (AIH) has a wide spectrum of clinical presentations, ranging from asymptomatic disease, acute or chronic hepatitis, to fulminant hepatic failure, and is characterized by intrahepatic lymphocyte activation, interface hepatitis, circulating autoantibodies, hypergammaglobulinemia, and a favorable response to immunosuppression. 1In concordance with other autoimmune diseases, AIH is associated with non-organ-specific antibodies (Abs), such as antinuclear Abs, in the context of hepatic
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