| Summary: | Thesis (M.Sc.)--Memorial University of Newfoundland, 2010. Medicine Includes bibliographical references (leaves 92-96) Almost all T cells normally express CD5, a transmembrane protein that regulates signaling through the T cell receptor (TCR). CD5 expression on T cells may be tuned to the avidity of TCR interactions with their cognate peptide/ major histocompatibility molecule complex (MHC). In transgenic mouse model systems, T cells expressing receptors with high avidity for self peptides escape negative selection if they have high levels of CD5. Conversely, peripheral T cells with low CD5 levels selectively react with cancer cells expressing low levels of cognate peptide MHC complexes. In human immunodeficiency virus (HIV) infection, CD5 expression is reduced on CD8+ T cells and there is evidence of abnormal CD8+ T cell cross-reactivity. The role of CD5 as a suppressor of TCR signaling suggests that its down-regulation in HIV infection may influence CD8+ T cell cross-reactivity. Our hypothesis is that HIV mutation generates CD8+ T cell epitope variants with lower avidity TCR interactions and that CD5 is down-regulated on memory T cells in adaptation. To test whether the avidity of TCR-peptide/MHC interaction correlates with CD5 expression on CD8+ T lymphocytes, T cell stimulation with non-HIV and HIV-derived peptides spanning 1000 fold range in avidity was carried out. Non-HIV infected controls were tested against Cytomegalovirus (CMV), Influenza (FLU), Epstein Barr virus (EBV) and self peptides. HIV-infected individuals were tested against the same set of peptides and a series of HIV peptides. CD8+ T cells proliferating against different peptides were identified by dilution of carboxyfluorescein diacetate succinimidyl ester (CFSE) fluorescence intensity and co-stained for CD8 and CD5 In controls and HIV-infected individuals, higher proportions of CD8+ T cells against non-HIV peptides with high TCR-peptide/MHC interaction avidities expressed CD5. In general, lower proportions of CD8+ T cells against HIV-derived peptides expressed CD5, regardless of avidity. -- The data suggest that reduced CD5 expression is conducive to promiscuous activation of peptide specific cytotoxic T cells through lower avidity T cell receptor interactions. With reduced CD5 expression there is a lower threshold for activation and T cells can be activated by cross-reactive peptides with lower avidity for the TCR than the index peptide (primary peptide used for initial activation). A greater understanding of this natural immunological occurrence could have potential therapeutic applications. Diseases regulated by cell mediated immunity, including HIV infection, could potentially be treated through control of T cell activation and signal modulation. The elucidation of CD8+ T cells lacking CD5 expression exclusively in HIV infected individuals could help scientists unravel new methodologies for treatment.
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