This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We hypothesized that interaction between CD4+ T cells and professional antigen presenting cells (APCs) is insufficient in HCV infected individuals, and that the resultant failure to generate and maintain a robust CD4+ T helper response contributes to viral persistence through alteration of the CD8+ T cell effector response. We successfully characterized the phenotype of HCV specific T cells and found the cells expressed high levels of PD-1 and low levels of CD127, an exhausted phenotype correlating with poor effector function. These cells are also uniquely susceptible to apoptosis. Recently we showed that these cells co-express the costimulatory molecule CD 86 during acute infection but rapidly lose this expression with the transition to viral persistence. This suggested that the balance between co-stimulatory and co-inhibitory molecules early in infection may influence infection outcome. We identified a complete panel of HCV epitopes to which HCV specific T cells should respond which will now allow for identification of specific immune deficits that may be targets for immune augmentation. Together, these studies have helped unravel the interplay between the APC and the T cell and elucidate mechanistic failures in the antiviral response. We recently submitted two manuscripts showing, in our murine model systems, that intrahepatic APC and specifically, hepatic stellate cells (HSC) are critical mediators of the intrahepatic immune response. HSC are the cell type responsible for fibrosis in chronic HCV infection;however, we recently showed that in the presence of TGFb, and in a retinoic acid-dependent manner, they contribute to the development of Tregulatory cells. We continue to dissect the molecular mechanisms responsible for these important observations.
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