Long‐Term Allograft Tolerance Is Characterized by the Accumulation of B Cells Exhibiting an Inhibited Profile

Numerous reports have highlighted the central role of regulatory T cells in long‐term allograft tolerance, but few studies have investigated the B‐cell aspect. We analyzed the B‐cell response in a rat model of long‐term cardiac allograft tolerance induced by a short‐term immunosuppression. We observed that tolerated allografts are infiltrated by numerous B cells organized in germinal centers that are strongly regulated in their IgG alloantibody response. Moreover, alloantibodies from tolerant recipients exhibit a deviation toward a Th2 isotype and do not activate in vitro donor‐type endothelial cells in a pro‐inflammatory way but maintained expression of cytoprotective molecules. Interestingly, this inhibition of the B‐cell response is characterized by the progressive accumulation in the graft and in the blood of B cells blocked at the IgM to IgG switch recombination process and overexpressing BANK‐1 and the inhibitory receptor Fcgr2b. Importantly, B cells from tolerant recipients are able to transfer allograft tolerance. Taken together, these results demonstrate a strong regulation of the alloantibody response in tolerant recipients and the accumulation of B cells exhibiting an inhibited and regulatory profile. These mechanisms of regulation of the B‐cell response could be instrumental to develop new strategies to promote tolerance. The authors show, in a rat model of cardiac allograft tolerance, that the B cell response is strongly regulated, and characterized by a deviation of the alloantibody response, B cell accumulation in the graft, and accumulation of peripheral blood B cells blocked at the switch recombination process that overexpress inhibitory molecules and can transfer tolerance. See editorial by Newell and Chong on page 420.