Regeneration and tolerance factor controls bystander depletion in HIV and IL-1beta secretion by regulating activation of the P2X7 receptor

Regeneration and Tolerance Factor (RTF) is a protein that is found on T cells, B cells, and Macrophages. It was cloned from mouse T cell line A1.1. RTF expression is increased on lymphocytes during HIV infection, or during general activation. RTF is an apoptosis related protein, in that antibody to RTF will induce apoptosis in cells that express it. RTF itself is a 70 kDa molecule that can be cleaved into a 50 kDa membrane bound form. The location of RTF has been mapped to chromosome 12. RTF is the α2 isoform of the α subunit of the vacuolar ATPase, a subunit with which there has been regulatory activity associated.; The data in this thesis show that RTF is involved with controlling immune activation and inflammation by regulating the activity of the P2X7 purinoceptor. It is also involved with preventing bystander depletion of T cells during HIV infection. During HIV infection, secondary infections cause ATP to be released, which interacts with the P2X7 receptor causing apoptosis and cell depletion. In this thesis, it is shown that RTF regulates vacuolar ATPase activity on the surface of the cell. This regulation is shown to prevent P2X7 induced apoptosis. RTF is also shown to be upregulated to the cell surface in an altered form that exists in the cytoplasm. This altered form of RTF is consistent with activation of the ATPase. RTF is also shown to regulate IL-1β secretion by controlling apoptosis and oncosis, suggesting a novel mechanism by which this leaderless cytokine can be secreted. These data indicate that RTF has an important role in regulating activation and the inflammatory response.