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Title: The role of CD5 in T lymphocyte activation
Author: Lacey, Erica
ISNI:       0000 0004 2717 4369
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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In order to prevent autoimmune diseases the immune system must be tightly regulated. One mechanism that the immune system uses to prevent autoimmunity is through the use of regulatory receptors on the surface of T lymphocytes. In this thesis I have concentrated on the role of one such receptor, CD5, in T lymphocyte activation. CD5 is a member of the scavenger receptor cysteine rich superfamily and is expressed, along with the closely related CD6, on T cells and a subset of B cells. CD5 is known for its inhibition of thymocyte selection but its function in peripheral T cell activation remains unclear. In this thesis I demonstrate that OX19, a rat CD5 monoclonal antibody (mAb), will block extracellular engagement of CD5 in vitro resulting in an increase in proliferation following T cell activation. In demonstrating the mode of action of OX19 I show that extracellular engagement of CD5 will inhibit T cell activation in vitro. I also demonstrate that OX19 does not modulate CD5 from the surface in vitro whereas it does modulate CD5 in vivo. Another key finding in this thesis is that differential phosphorylation of the three tyrosines in the CD5 cytoplasmic tail can account for positive and negative signalling by CD5 during T cell activation. Evidence here demonstrates that CD5 Y1 is required for positive signalling which becomes more apparent in the absence of costimulation by the coreceptor, CD2. CD5 Y2 and Y3 are required for the CD5 mediated inhibition of T cell activation. Phosphorylation of these tyrosines is also necessary for CD5 regulation of CD3 down modulation following TCR triggering. These data point to a potential molecular mechanism involving CD5 regulation of CD3 down modulation creating control of T cell activation as well as a potential for cross talk between another coreceptor CD2. Direct and indirect associations of the phosphorylated tyrosines in CD5 was analysed here using a combination of a screen of binding affinities of SH2 domains with CD5 phospho-peptides and mass spectrometry of CD5 associated proteins. SH2 domains measured in this thesis did not show a high binding capacity to tyrosine phosphorylated CD5 peptides indicating that CD5 mediates transient interactions with signalling proteins. The region in the cytoplasmic tail in CD6, CD6Y3Y4, which lies at the same distance from the membrane as the C-terminus of CD5, will bind to Itk and Lck. Given CD5 and CD6 are often coexpressed this would allow phosphorylation of CD5 by these two kinases providing a molecular mechanism underlying cooperation between CD5 and CD6.
Supervisor: Brown, Marion H. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Life Sciences ; Immunochemistry ; Multiple Sclerosis ; Biology ; Medical Sciences ; Immunology ; Mass spectrometry ; Membrane proteins ; T Lymphocyte ; Scavenger Receptor Cysteine Rich ; Signalling ; Tyrosine Phosphorylation