B cells are required for CD8 T cell recovery after antibody-mediated depletion (TRAN3P.895)

Antibody-mediated lymphoablation is used as an induction therapy in transplant patients. We investigated the requirements for T cell recovery following lymphoablation in a mouse model of heart transplantation. Memory CD4 T cells are less susceptible to depletion by murine antithymocyte globulin (mATG) than CD8 T cells. Additional CD4 T cell depletion impaired CD8 T cell recovery after mATG treatment in B6 recipients of BALB/c heart allografts and in non-transplanted B6 mice. Treatment with blocking anti-CD154 mAb plus mATG inhibited CD8 T cell recovery, while agonistic anti-CD40 mAb restored memory CD8 T cell expansion after mATG treatment of CD4 T cell depleted recipients. To test whether B cells are required for CD8 T cell recovery, we used B6.huCD20tg mice. Treatment with anti-human CD20 mAb depleted >90% of peripheral B cells and markedly inhibited CD8 T cell expansion in huCD20tg recipients compared to B cell-sufficient mice. Next, B cells were isolated from mATG treated recipients with or without CD4 depletion. In the absence of CD4 T cells, B cells expressed lower levels of MHC class I, CD80, CD86, and TNFα suggesting that both cognate interactions and cytokines promote CD8 T cell expansion. Our results show that CD4 T cell help mediated through B cells and CD40/CD154 interactions drives CD8 T cell reconstitution following antibody-mediated depletion. These findings may be used to improve the efficiency of lymphoablation in sensitized transplant recipients.