T cell Tolerance - Cellular and molecular features of immune regulation

Abstract: The immune system has evolved regulatory mechanisms in order to balance the effects of deleterious immune responses. Such immunological tolerance may be specifically acquired by lymphocytes, although different cells of the immune system participate in the induction and maintenance of tolerance. This thesis work is based on investigations of different tolerance mechanisms induced in CD4+ T lymphocytes in vivo. T cell activation or tolerance has been experimentally induced in TCR-transgenic mice in order to study T cell tolerance both at the cellular and molecular level. The tolerant state of CD4+ T cells is characterised by deficient production of the growth factor IL-2 as well as a reduced proliferation. We have found that the activity of the transcription factor NFkB is altered in tolerant T cells and that this may contribute to the reduced expression of IL-2. Moreover, the ability of tolerant CD4+ T cells to respond to IL-2 is impaired and this is related to decreased activity of the JAK/STAT pathway downstream the IL-2 receptor. We have also shown that CD4+ T cells with regulatory functions may be induced after tolerance induction in vivo. These regulatory T cells down-modulate the expression of costimulatory molecules on APCs and suppress the activation of naive T cells in vitro. In contrast to CD4+ T cells, CD8+ T cells are less susceptible to tolerance induction and thus retain their cytotoxic capacity. These results contribute to the understanding of how immune tolerance is achieved.