| Although there is considerable evidence that a subpopulation of T cells (CD4+CD25+, T-reg) can suppress the responses of auto-reactive T cells, the underlying molecular mechanism is not understood. My interest at the outset of this work was to elucidate the mechanisms whereby T-reg suppress the responses of other T cells. This thesis summarizes data which demonstrates that the responses of T helper (Th) cells from B7-KO mice are resistant to suppression in vitro and these cells provoke a lethal wasting disease in lymphopenic mice despite the presence of T-reg. Susceptibility of B7-KO Th cells to suppression is restored by lentiviral-based expression of full-length but not truncated B7 lacking its trans-membrane and cytoplasmic domain. In addition, monoclonal antibodies to B7.1 and B7.2, but not isotype control antibodies, exerted suppressive activity separately and combined to efficiently inhibit the responses of B7-WT-CD28-KO and B7-WT-CD28-WT CD4+CD25- cells. In contrast, responses of B7-KO Th cells are unaffected even by the highest antibody concentrations tested, and that suppression is independent of the B7 genotype of antigen presenting cells (APC). Therefore, B7-mediated transmission of suppressive signals regulates T cell responses, and that complete co-stimulatory blockade is neither necessary for nor relevant to the suppressive activity herein described.; It is now clear that B7-mediated co-stimulation is required for the maintenance of a functional T-reg repertoire. To test whether B7-mediated co-stimulation of T-reg is insufficient in the regulation of autoimmune disease, co-stimulation, either in form of activated B7-WT APC, or by generating mixed bone marrow chimera (BMC) mice, was provided to B7-KO T cells. Administration of co-stimulation resulted in T cell activation and lympho-proliferative disease despite the presence of functional T-reg, which potently suppressed B7-WT, but not B7-KO Th cells. In addition, B7-KO-2D2-TCR transgenic BMC mice, which harbor B7-WT APCs and Th cells specific for an encephalitogenic oligodendrocyte glycoprotein (MOG) peptide, present with lethal experimental autoimmune encephalomyelitis (EAE), while B7-WT-2D2-TCR Tg BMC mice do not. Therefore, B7-signaling activity on Th cells is dominant over B7-mediated co-stimulation of T-reg in the regulation of autoimmune disease. |
