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TitleCD5 expression levels and human immunodeficiency virus-specific T cells
AuthorPenney, Stephen John, 1982-
DescriptionThesis (M.Sc.)--Memorial University of Newfoundland, 2010. Medicine
Date2010
Paginationxii, 96 leaves : col. ill.
SubjectCD antigens; HIV infections--Immunological aspects; T cells--Receptors;
Subject.MESHAntigens, CD5; HIV Infections--immunology; Receptors, Antigen, T-Cell;
DegreeM.Sc.
Degree GrantorMemorial University of Newfoundland. Faculty of Medicine
DisciplineMedicine
LanguageEng
NotesIncludes bibliographical references (leaves 92-96)
AbstractAlmost 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.
TypeText
Resource TypeElectronic thesis or dissertation
FormatImage/jpeg; Application/pdf
SourcePaper copy kept in the Centre for Newfoundland Studies, Memorial University Libraries
Local Identifiera3496875
RightsThe author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
CollectionElectronic Theses and Dissertations
Scanning StatusCompleted
PDF File(12.67 MB) -- http://collections.mun.ca/PDFs/theses/Penney_StephenJohn.pdf
CONTENTdm file name42333.cpd