A central role of T/B cell collaboration in the genesis of autoimmune diabetes

Autoimmunity in the NOD mouse is a paradigm of dysregulated T cell tolerance where anti-islet T cells selectively destroy pancreatic β cells causing diabetes. This breakdown of T cell tolerance results from a sequence of events beginning with the thymic positive selection of a repertoire containing islet-reactive T cells. The present work is focused on elucidating the mechanisms which allow peripheral anti-islet T cells to differentiate into diabetogenic effectors.; By characterizing B cell deficient NOD mice, the presented studies established that B lymphocytes are required for the progression of T cell mediated anti-islet autoimmunity. More specifically, the contribution of B cell mediated antigen presentation to the activation of diabetogenic T cells was assessed. NOD mice with a selective MHC class II deficiency confined to the B cell compartment were generated. These mice were resistant to spontaneous autoimmune diabetes demonstrating a central role of B cell APC function in mediating the activation of a diabetogenic T cell response. Consistent with this finding, a series of in vitro studies demonstrated the dependence of NOD CD4 T cell activation upon B cell costimulation. Specifically, B cell mediated cognate costimulation was found to be required for driving anti-CD3 mediated NOD CD4 T cell activation. This finding suggested that B cells may be more competent than the non-B cell APC compartment at providing the costimulation necessary for anti-CD3 mediated CD4 T cell activation in NOD mice. The stringent dependence of CD4 T cell activation on B cell costimulation in NOD mice is characterized by: (1) an increased TCR stimulus threshold required for triggering activation and (2) a premature termination of division. An increase in the stimulus threshold required for CD4 T cell activation could protect a range of antigen-reactive TCR specificities from activation-induced regulation. Furthermore, the prematurely aborted process of cell division does not allow activated NOD CD4 T cells to efficiently achieve the threshold number of divisions required for susceptibility to activation-induced deletion. Thus, in NOD mice, B cells appear to be most competent at delivering the costimulation required for CD4 T cell activation. This cognate B cell mediated CD4 T cell costimulation, while sufficient for activation of diabetogenic T cells, may not promote optimal activation-induced regulation of NOD CD4 T cells.