Some studies on human aB+ and yd+ T lymphocytes in health and disease

T lymphocytes use the T cell receptor (TCR) to specifically recognize antigens. According to the type of TCR heterodimer, T cells can be phenotypically divided into a B+ or yd+ subsets. In many human inflammatory/autoimmune diseases significant expansions of aB+ and yd+ T cells have been described. Interestingly, in most of these diseases several microorganisms (including mycobacteria) are suspected as causative agents. In this thesis quantitative and qualitative studies of human T lymphocytes, with particular interest in TCR V usage, were performed. Initially, the frequency and distribution of TCR aB+ and yd+ T lymphocytes in healthy humans were studied. The existence of a site-specific TCR VB distribution pattern, different from that of peripheral blood, was demonstrated in the healthy human gut.

Significantly higher yd+ T cell levels in peripheral blood were detected in the Asian and Turkish groups as compared to Swedish and Japanese groups. These results suggest a possible influence of environmental antigenic exposure in the form of infections on the distribution and frequency of aB+ and/or yd+ T cells among healthy adults. Behcet's disease (BD) is a chronic multisystemic inflammatory disorder with unknown etiology. Most of the immunological studies suggest a central role for T cells in the pathogenesis of BD. In our study, significant oligoclonal expansions of peripheral blood T cells were recorded in BD patients. All aB+CD4+ T cell expansions correlated with disease activity.

The observed restricted V and J gene usages in the T cell expansions are consistent with a response to a conventional antigen and suggest a possible involvement of antigen-specific T lymphocytes in the pathogenesis of BD. To investigate the interactions between T-cells and an infectious agent, we then explored, by use of an in vitro infection model, the proliferative response of human peripheral blood T cells from healthy adults upon stimulation with mycobacteria. Cell proliferation was evaluated by a novel flow cytometric technique which allows direct identification of phenotype of the proliferating cells within complex cell populations. In response to various mycobacterial antigen preparations, proliferation of distinct (T) cell subsets (yd+, aB+CD8+, aB+CD4+, NK cells) was recorded. In order to explore if the T cell proliferation was associated with particular TCR V usage we subsequently analysed TCR Va/VB expression upon in vitro stimulation with M tuberculosis. Expansion of CD4+Va2.3+ T cells with preference to short CDR3-lengths was recorded in HLA-DR17(3)+ healthy individuals. Interestingly, Va2.3+ T cell expansions in broncho-alveolar lavage fluid from HLA-DR17(3)+ sarcoidosis patients have been reported. Such similarity in expanded T cell populations might suggest a mycobacterial involvement in the pathogenesis of sarcoidosis. The present findings are discussed in the context of infectious organisms playing a significant role in the regulation and restriction of human TCR repertoire in health and autoimmune diseases.