Cook, Joanne Elizabeth; (2003) Clonal analysis of CD4+ T cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Responses of T cells to antigen depend on recognition of MHC-peptide complexes by cells with specific clonal T cell receptors. There is much data on the properties of individual clones responding to particular peptide-MHC complexes of infectious agents and also data analysing the TCR sequence variability of T cells responding to single peptide-MHC complexes. However, there is less data on global responses and the size and number of clones. Most studies to date have focussed on CD8+ T cells where large expanded clones have been detected in a number of cell populations, helping to define clonal responses to a range of infections. In contrast there is limited data in CD4+ cells where clones are much smaller and are present at a lower frequency. The data presented in this thesis examines the clonality of CD4+ T cells at a global level through heteroduplex analysis. Initial attempts to establish this technique for examination of clonality in mice failed; however the technique is proven in human studies. Human CD4+ cells were subdivided by their expression of CD45, CD27 and CD95 to determine which phenotypic markers distinguish naive, memory and effector cells. Phenotypic and clonal analysis have allowed a model of differentiation to be proposed suggesting that loss of CD27 and acquisition of CD95 defines antigen experienced cell populations. Data also suggests that a population of CD45RA+CD27' CD95+ cells might be a revertant population. The clonality of CD4+CD45R0+CD25+ regulatory cells has also been examined. There was a large overlap in clonality between CD25+ and CD25' cells suggesting that regulatory T cells may develop in the periphery from antigen experienced cells. Studies in humans are mostly performed on peripheral blood samples due to ethical and practical constraints of sampling tissues. The data presented here examines the overlap of clonality of cells in blood, secondary lymphoid tissues and non-lymphoid effector tissues, and shows that there is a high degree of overlap in clonality between blood and tissues. Collectively, these data provide further knowledge of the clonal responses of CD4+ cells.

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