Transitional‐2 B cells acquire regulatory function during tolerance induction and contribute to allograft survival

In humans, tolerance to renal transplants has been associated with alterations in B‐cell gene transcription and maintenance of the numbers of circulating transitional B cells. Here, we use a mouse model of transplantation tolerance to investigate the contribution of B cells to allograft survival. We demonstrate that transfer of B cells from mice rendered tolerant to MHC class I mismatched skin grafts can prolong graft survival in a dose‐dependent and antigen‐specific manner to a degree similar to that afforded by graft‐specific regulatory T (Treg) cells. Tolerance in this model was associated with an increase in transitional‐2 (T2) B cells. Only T2 B cells from tolerized mice, not naïve T2 nor alloantigen experienced T2, were capable of prolonging skin allograft survival, and suppressing T‐cell activation. Tolerized T2 B cells expressed lower levels of CD86, increased TIM‐1, and demonstrated a preferential survival in vivo. Furthermore, we demonstrate a synergistic effect between tolerized B cells and graft‐specific Treg cells. IL‐10 production by T2 B cells did not contribute to tolerance, as shown by transfer of B cells from IL‐10−/− mice. These results suggest that T2 B cells in tolerant patients may include a population of regulatory B cells that directly inhibit graft rejection.