I-A(g7)-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice

B cell-deficient nonobese diabetic (NOD) mice are protected from the develo pment of spontaneous autoimmune diabetes, suggesting a requisite role for A g presentation by B lymphocytes for the activation of a diabetogenic T cell repertoire. This study specifically examines the importance of B cell-medi ated MHC class II Ag presentation as a regulator of peripheral T cell toler ance to islet beta cells. We describe the construction of NOD mice with an I-A(g7) deficiency confined to the B cell compartment. Analysis of these mi ce, termed NOD B-CIID, revealed the presence of functionally competent non- B cell APCs (macrophages/dendritic cells) with normal I-A(g7) expression an d capable of activating Ag-reactive T cells. In addition, the secondary lym phoid organs of these mice harbored phenotypically normal CD4(+) and CD8(+) T cell compartments. Interestingly, whereas control NOD mice harboring I-A (g7)-sufficient B cells developed diabetes spontaneously, NOD B-CIID mice w ere resistant to the development of autoimmune diabetes, Despite their diab etes resistance, histologic examination of pancreata from NOD B-CIID mice r evealed foci of noninvasive peri-insulitis that could be intentionally conv erted into a destructive process upon treatment with cyclophosphamide. We c onclude that I-A(g7)-mediated Ag presentation by B cells serves to overcome a checkpoint in T cell tolerance to islet beta cells after their initial t argeting has occurred. Overall, this work indicates that the full expressio n of the autoimmune potential of anti-islet T cells in NOD mice is intimate ly regulated by B cell-mediated MHC class II Ag presentation.