Cell-intrinsic Transforming Growth Factor-β signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo (39.12)

Abstract

Abstract Chronic viral infections represent a major biomedical problem. Although, in both humans and mice, viral persistence has been associated with insufficient numbers and/or function of CD8+ T cells, the underlying mechanisms are still unclear. By using Lymphocytic choriomeningitis virus in its natural murine host, we found that enhanced and sustained Transforming Growth Factor-β (TGF- β),expression and phosphorylation of its signaling mediator, Smad-2, were distinctive features of virus-specific CD8+ T cells during chronic versus acute viral infections in vivo. Selective attenuation of TGF-β pathway in T cells decreased the expression of the pro-apoptotic protein Bim and increased survival and numbers of virus-specific CD8+ T cells. Under these conditions, virus-specific CD8+ T cells had enhanced cytotoxicity, increased production of anti-viral cytokines, and down-regulation of inhibitory molecules. The end result was rapid virus eradication and generation of an effective memory T cell response that protected the host upon subsequent challenge. Notably, we found that cell-intrinsic TGF-β signaling was responsible for virus-specific-CD8+ T cell apoptosis but was not necessary for their functional exhaustion. Our findings demonstrate that sustained TGF-β-Smad signaling is a hallmark and master regulator of CD8+ T cell responses during chronic viral infections in vivo.