CD4+ T cells from fibrotic livers direct aberrant autoantibody production from B cells (HUM1P.308)

Abstract Two of the most common causes of end-stage liver disease (ESLD) are hepatitis C virus (HCV) infection and alcoholic liver disease (ALD); the only therapeutic option for liver failure is a liver transplant. Extrahepatic manifestations of ESLD include antibody-mediated autoimmunity; an indication of B cell and CD4+ T cell dysfunction. To investigate the contribution of CD4+ T cells during liver disease, we induced liver fibrosis in mice by a conventional weekly carbon-tetrachloride treatment regimen. Fibrotic animals show elevated serum IgG, positive ANA titers and spontaneous IgG production from hepatic B cells. However, this was not evident in CD4+ T cell depleted fibrotic animals despite comparable fibrosis by pathology. Despite significant expression of Foxp3 on fibrotic liver CD4+ T cells, concomitant expression of CD27, PD-1 and CD40L may account for their ability to promote B cell activation. To understand the implications during ESLD in humans, we performed parallel analysis from human liver explant samples. In accordance with our fibrotic mouse model, we saw an enrichment of Foxp3+ CD4+ T cells as well as spontaneous IgG production that was not evident in healthy liver or PBMC. Taken together, these data suggest that altered hepatic CD4+ T cells aberrantly instruct B cells to drive extrahepatic sequelae of ESLD.