Regulation of IL-7 receptor (CD127) expression on circulating CD8+T cells in HIV infection and its role in cytotoxicity

The progressive breakdown of cell mediated immunity is a feature in the pathology of HIV disease. Although not lost from the circulation, with disease progression cytotoxic T lymphocytes (CTL) are less able to contain numerous pathogens including HIV itself. Interleukin (IL)-7 and its signalling via the IL-7 receptor (CD127) is essential for optimal CTL activity. Our demonstration that fewer CD8+ T cells from HIV+ patients express CD127 as compared to healthy individuals, implicates a role for the regulation of CD127 expression in the immunopathogenesis of HIV. Thus, we hypothesize that altered CD127 expression and/or function on CD8+ T cells contributes to impaired cell mediated immunity. This thesis reports an examination of which host or viral factors may be responsible for the down-regulation of CD127 on CD8+ T cells in HIV infection and the mechanism(s) by which these host and/or viral factors decrease CD127 expression on CD8+ T cells. It also assesses whether HIV down-regulates CD127 expression on CD8+ T cells in vitro, and evaluates if the functional capacity of CD127 is altered in HIV infection. Of all the host and viral factors tested, IL-7, IL-4 and HIV-1tat caused a down-regulation in surface CD127 expression on CD8+ T cells, without affecting CD127 mRNA. IL-7 did not increase internalization of surface CD127, but caused shedding of the receptor. Furthermore, In vitro HIV infection of PBMC caused a down-regulation in surface CD127 expression on CD8+ T cells, without affecting CD127 mRNA, and seems to be caused by a soluble factor produced by the infected PBMCs. Finally, in response to IL-7, STAT5 phosphorylation in CD8+CD127 + cells from HIV+ individuals is significantly decreased compared to healthy controls. Proliferation of CD8+CD127 + cells in response to IL-7 is also significantly impaired. These data demonstrate a dysfunction in the IL-7 receptor system that may be explained by IL-7 specific signal transduction defects. As the IL-7/IL-7R system and its disruption during HIV infection continue to be intensively studied, one will get a better understanding of HIV immunopathogenesis and the potential to lead to the development of novel immune based therapies will come about