Factors regulating lymphocyte development and peripheral activation

Abstract: Peripheral tolerance is regulated by different types of regulatory T cells, including CD1-restricted T cells and CD4+CD25+ regulatory T (Treg) cells. This thesis has focused on the interactions between T cells and antigen presenting cells (APCs) and the immunregulatory function of TGF-b as two important factors regulating differentiation and activation of T cells in the periphery. In the first part of the study we characterized a subset of B cells expressing high levels of CD1, reasoning that they could represent the potential APCs for CD1-restricted T cells. These B cells had a phenotype of marginal zone B cells and localized preferentially to the spleen. They appear late in ontogeny and are involved in both T cell dependent and T cell independent immune responses. We also compared the ligand specificity of two sub-populations of CD1d-restricted T cells with a diverse and limited TCR repertoire. T cell hybridomas representing these two subpopulations showed distinct pattern of reactivity to the differently glycosylated ceramides. Hybridomas with a diverse TCR did not recognize any of the tested glycoceramides, while those with a restricted TCR reacted to a-galactosylceramide and its variants in a anomeric configuration. These results suggest that CD1d-restricted T cells with a diverse and limited TCR repertoire are involved in distinct types of immune responses. In the second part of the thesis we investigated the role of APCs in the suppressive function of Treg cells and found that co-culture of both types of cells resulted in rapid, CTLA-4-dependent down-modulation of costimulatory molecules on APCs. This effect correlated with the suppression of CD4+ responder T cells and addition of anti-CTLA-4 neutralizing antibody restored the proliferative response of these cells. Finally, we also examined the involvement of TGF-b signaling in the development of T cells. Analysis of TbRII inducible knockout mice demonstrated that the absence of TbRII does not effect T cell differentiation, but it increases the proliferation capacity of maturing T cells. These results suggest that the TGF-b signaling pathway can regulate the expansion of selected T cell subsets.