Role of regeneration and tolerance factor RTF in human T cell activation and apoptosis (Immune deficiency)

RTF is a protein that is found on B and T lymphocytes in HIV infected individuals by flow cytometry. In HIV infected individuals, T lymphocytes that expressed surface RTF co-expressed the activation markers HLA-DR and CD38. HCV infected individuals do not express RTF or the activation markers HLA-DR and CD38 on the surface of T lymphocytes. Regeneration and tolerance factor (RTF) was cloned from a mouse T cell line, A1.1. Early findings localized RTF expression to the developing tissues of the placenta and thymus. The RTF gene maps to the long arm of human chromosome 12. The RTF protein has a soluble N-terminus and a membrane bound C-terminus that contains a protein kinase C site in the cytoplasmic tail.; The data in this thesis show that the in vitro activation of T lymphocytes increases the surface expression of RTF. Maximal RTF surface expression on T lymphocytes occurs at 48 hr, after the early T lymphocyte marker CD69 and before the late T lymphocyte marker CD25 (IL-2 receptor). RTF surface expression statistically correlated with the upregulation of CD95 (Fas receptor) and CD25 after T lymphocyte activation. RTF surface expression occurs after TCR complex ligation alone and does not require co-stimulation. The activation of T lymphocytes by T cell receptor complex ligation in the absence of co-stimulation produces a state of anergy. Lastly, we show that a monoclonal antibody to RTF induces apoptosis in Jurkat T cells and PBMC derived T lymphocytes. Anti-RTF induces unactivated and 24 hr anti CD3E and anti-CD28 activated T lymphocytes to undergo apoptosis unlike anti-CD95 mediated apoptosis. When RTF is highly expressed on T lymphocytes, the cells do not undergo as much anti-RTF mediated apoptosis. Both anti-RTF and anti-CD95 activate caspase 3 and caspase 8. Unlike anti-CD95 mediated apoptosis, anti-RTF mediated apoptosis does not occur in the absence of divalent cations. These data suggest that RTF is a novel T lymphocyte associated activation antigen and mediates apoptosis in both unactivated and activated T lymphocytes. RTF may be rapidly upregulated on anergic T lymphocytes allowing for the generation of tolerance by protection from apoptosis.