Long-Term Control of Alloreactive B Cell Responses by the Suppression of

Alloantibodies can play a key role in acute and chronic allograft rejection. However, relatively little is known of factors that control B cell responses following allograft tolerance induction. Using 3-83 Igi mice expressing an alloreactive BCR, we recently reported that allograft tolerance was associated with the sustained deletion of the alloreactive B cells at the mature, but not the immature, stage. We have now investigated the basis for the long-term control of alloreactive B cell responses in a non-BCR-transgenic model of C57BL/6 cardiac transplantation into BALB/c recipients treated with anti-CD154 and transfusion of donor-specific spleen cells. We demonstrate that the long-term production of alloreactive Abs by alloreactive B cells is actively regulated in tolerant BALB/c mice through the dominant suppression of T cell help. Deletion of CD25! cells resulted in a loss of tolerance and an acquisition of the ability to acutely reject allografts. In contrast, the restoration of alloantibody responses required both the deletion of CD25! cells and the reconstitution of alloreactive B cells. Collectively, these data suggest that alloreactive B cell responses in this model of tolerance are controlled by dominant suppression of T cell help as well as the deletion of alloreactive B cells in the periphery. The Journal of Immunology, 2008, 180: 6077–6084. I t is widely appreciated that alloantibodies can play a key rolein acute and chronic allograft rejection. However, relativelylittle is known of factors that control B cell responses fol-lowing allograft tolerance induction. Indeed, most investigations of the induction of allograft tolerance have focused on the regu-lation of T cell responses (1–4). We hypothesize that control of