Lightstone, Elizabeth Beatrice; (1993) Characterization of the murine T cell subsets defined by CD45RA isoforms. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

T cells are functionally and phenotypically heterogenous. Correlation of phenotype with function allows the possibility to elucidate the contribution of T cell subsets in an immune response and opens an avenue towards more specific immunotherapy in autoimmunity and transplantation. A particular goal has been to phenotypically identify naive and memory T cells. In vitro studies in humans had suggested that expression of the heavy molecular weight isoforms (CD45RA) of CD45, a phosphotyrosine phosphatase, defined naive T cells. The studies in this thesis set out to determine if comparable subsets could be identified in the mouse with the aim of dissecting out the mechanisms involved in the generation of immunological memory. However, it became apparent that CD45RA did not simply define naive T cells. Three anti CD45RA antibodies were shown to split both CD4+ and CD8+ mouse T cell subsets into CD45RA+ and CD45RA- populations. Assessment of CD45RA as a marker of naive cells involved determining phenotype in vivo at all stages of maturation and differentiation as well as functional assessment in vitro and in vivo of purified CD4+ or CD8+ CD45RA+ and CD45RA- subsets. CD45RA defines a minority population of thymocytes which, particularly among CD4+ cells, is too small to account for all thymic emigrants. In the periphery, among CD4+ cells the CD45RA+ subset is maintained after thymectomy, with ageing and following transfer and expansion in irradiated hosts, again suggesting CD45RA is not a marker of naive cells. Indeed, in vivo CD4+CD45RA+ cells can provide help for secondary responses in an adoptive transfer assay, albeit not as well as the reciprocal subset. Among CD8+ cells there is a modest decline in the proportion of CD45RA+ cells with ageing, thymectomy and cell transfer suggesting that at least a fraction is naive. Functionally, in vitro, CD8+CD45RA+ cells behave as if naive when primary and secondary CTL responses to alloantigen are assayed. However, in vivo studies on T cell receptor transgenic mice show that CD45RA expression is not confined to naive cells. Lack of appropriate costimulation is postulated to account for the differences between the in vitro and in vivo findings. The CD4+CD45RA+ subset is hypo-responsive to stimulation with PHA or anti CD3 in vitro in the absence of appropriate costimulatory signals. Furthermore, the subsets differ in their cytokine production. Overall the data suggest that expression of CD45RA correlates with the state of activation of a cell rather than its antigenic history and that the ratio of CD45RA+ to CD45RA- cells is tightly controlled.

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