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Title: Defective CD4+ T cell activation in the presence of a metalloproteinase inhibitor
Author: Savage, N. D. L.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2001
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This thesis investigated the contribution of Zn2+ metalloprotein enzymes to human and murine CD4+ T cell activation. The experiments described here reveal that addition of a hydroxamate pseudopeptide, BB-3103, capable of inhibiting a broad range of metalloproteinases, to selected T cell proliferation assays, reduced the T cell responses by up to 40% compared to the control. B cell proliferation was not affected suggesting the metalloproteinase activity on lymphocytes is targetted specifically to CD4+ T cells. Phenotypic analysis of activated CD4+ T cells revealed that two markers were differentially expressed in the presence of BB-3103, CD27 (a co-stimulatory molecule of the TNFR family highly expressed on CD4+ T cells) and CD62L (CD62L or L-selectin, an adhesion molecule mediating interaction between CD4+ T cells and endothelium). These molecules were not shed from the surface of the cell upon activation in the BB-3103 treated samples. CD4+ T cells isolated from CD62L knock out mice were not inhibited by the presence of BB-3103 and demonstrated deficient proliferation as compared to wild type controls even in the absence of the inhibitor. This data strongly suggested that expression of CD62L on the CD4+ T on the CD4+ T cells was necessary for complete activation. Cross-linking CD62L with monoclonal antibodies in a proliferation assay increased wild type CH4+ T cell response and could protect the lymphocytes from the proliferation inhibition previously observed. The presence of BB-3103 in proliferating T cells, reduced IL-2 secretion correlating exactly to the results obtained from CD4+ T cell proliferation assays. Signalling pathways of activated CD4+ T cells were investigated. Tyrosine phosphorylation of CD3ζ ITAM sequences and ZAP-70, two key signalling molecules was found to be dysregulated in the presence of BB-3103. Calcium ion mobilisation within activated CD4+ T cells was unregulated in the presence of BB-3103 which suggested that CD62L shedding plays an important role in regulating CD4+ T cell activation pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available