Ferreira, Christina de Conceicao Varandas; (2001) Naive T cell survival and homeostasis analysis of monoclonal and polyclonal T cell populations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Understanding the mechanisms that regulate life span and survival of the naive T cell clones that compose the peripheral pool is essential to understand the functioning of the immune system. In this study the survival characteristics of several individual monoclonal T cell populations, obtained from TCR transgenic mice, as well as polyclonal controls were analysed using different survival criteria. Initially, T cell life span was established for each population by monitoring T cell persistence after thymectomy. Subsequently susceptibility to apoptosis in vitro and homeostatic proliferation were also determined. It was observed that TCR transgenic CD4 T cells, when compared with CD8 T cells, have an intrinsically lower capacity for survival, which is reflected in their gradual disappearance in thymectomised hosts, their increased sensitivity to apoptosis in vitro and fewer divisions upon transfer into syngeneic lymphopenic hosts. Also in the case of polyclonal T cells, naive CD8 T cells appear to survive better than their CD4 counterparts, which is reflected in a drop of the CD4/CD8 ratio observed in old animals and in thymectomised animals, when compared with young controls. Homeostatic proliferation was not universally accompanied by phenotypic conversion of activation markers. Some T cells, such as A18 T cells, maintained a naive phenotype while dividing, whereas others, like AND T cells acquired a memory-like phenotype. It is currently unknown whether phenotypic conversion is a reflection of high avidity or indicates the presence of cross-reactive antigens in the host. In the second part of the project two other parameters were studied for their influence on T cell homeostasis. These were overexpression of an adhesion molecule on thymic epithelium (EVA molecule) or of CD4 co-receptor on A18 T cells. Although further work will still have to be performed on the subject, the data obtained suggests that both factors might affect the peripheral pool size. The larger peripheral pools found in both situations might be a consequence of increased thymic export, better cell survival resulting from more efficient imprinting of survival signals during thymic development or increased proliferative capacity associated with high avidity peripheral interactions.

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