Item – Theses Canada

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OCLC number
741397786
Link(s) to full text
LAC copy
LAC copy
Author
Varghese, Jay Cherian,1977-
Title
CD8 co-receptor and accessory molecule functions in CD8+ T lymphocytes.
Degree
Ph. D. -- University of Alberta, 2009
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2010]
Description
2 microfiches
Notes
Includes bibliographical references.
Abstract
The elimination of virally infected and malignant cells by cytotoxic T lymphocytes (CTL) involves antigen recognition, adhesion, and induction of target cell death. The cell surface glycoprotein CD8 plays a central role in CTL functions; in conjunction with the TCR, the CD8 co-receptor binds antigen-specific class I MHC (MHC-I) molecules expressed by target cells, initiating signaling events that result in T cell activation. Whether CD8 can further function as an adhesion molecule for non-antigen MHC-I was unknown in humans. We find that in human CD8+ T cells, TCR/CD3 complex signaling activates CD8 adhesion molecule function, resulting in CD8--non-antigen MHC-I interactions that are sufficient to maintain firm T cell adhesion under shear conditions. Secondly, we find that while CD8 adhesive function was triggered by TCR complex activation in differentiated cells, including 'in vitro ' generated CTL and 'ex vivo' effector/memory phenotype CD8+ T cells, naïve CD8+ T cells were incapable of activated CD8 adhesion. Lastly, we examine the kinetics of, and signaling for, activated CD8 adhesion in humans and identify notable differences from the equivalent CD8 function in mouse, but similarities to TCR complex-activated LFA-1 adhesion. The co-receptor and accessory adhesion molecule functions of murine CD8 were previously shown to differ with respect to the manner in which each bound to MHC-I; while MHC-I residue 227 is required for CD8 co-receptor binding, it is dispensable for TCR-activated CD8 adhesion. We identify the first residue (Q226 on the MHC-I [alpha]3 domain) known to be required for TCR-activated CD8 adhesion in mouse. We show that Q226 is also involved in CD8 co-receptor binding; therefore in mouse, both CD8 functions partially overlap with respect to the MHC-I surface bound. This suggests that the two forms of CD8--MHC-I interaction are likely not the result of a complete reorientation of binding surfaces since both appear to bind the same face of MHC-I. In extending our mapping studies to humans, we found an additional inter-species difference: unlike mouse, human TCR-activated CD8 adhesion to HLA does not appear to require residue Q226. It is likely that this discrepancy is a result of inter-species structural variations in CD8--MHC-I interactions, but it may also be due to mechanistic differences in activated CD8 adhesion between the two species.
ISBN
9780494556283
0494556285