Studies on the function of CD4CD25 regulatory T cells: An in vitro approach

Abstract: Immunological self-tolerance is a state of the whole organism where deleterious responses are either avoided or regulated. Breaking of immunological tolerance will lead to autoimmune disease or chronic inflammatory conditions. T cell maturation in the thymus generates a peripheral T cell pool with an enormous TCR repertoire, from which specific T cells are selected and activated upon encounters with pathogens. However, potentially autoaggressive T cells are also produced by the thymus. In order to prevent these autoreactive T cells from causing disease, the immune system has evolved several distinct mechanisms by which they are regulated. Recently, it has become apparent that regulatory T cells are crucial for the maintenance of self-tolerance. One such population of regulatory T cells, the CD4+CD25+ T cells, has been shown to regulate the induction of various autoimmune diseases. CD4+CD25+ T cells also suppress activation-induced proliferation of CD4+CD25- T cells in vitro. The aim of this thesis is to find out how CD4+CD25+ T cells function in vitro. We present data showing that the CD4+CD25+ T cell-mediated suppression of CD4+CD25- T cells in vitro, is strictly dependent on the presence of antigen-presenting cells. Moreover, we show that CD4+CD25+ T cells down-modulate the costimulatory molecules CD80 and CD86 on dendritic cells. We also demonstrate that the down-modulation of CD80 and CD86 on dendritic cells is sufficient for inhibiting the proliferation of CD4+CD25- T cells. Furthermore, we found that the down-modulation of CD80 and CD86 on dendritic cells is mediated by CD152 expressed by the CD4+CD25+ T cells. Together these data suggest that one major mechanism by which CD4+CD25+ T cells suppress proliferation of CD4+CD25- T cells in vitro, is by a CD152-mediated down-modulation of costimulatory molecules on antigen-presenting cells.