Defensive tolerance drives the reprogramming and dysfunction of infiltrating pathogenic B cells assuring the maintenance of tolerance.

We previously showed that infiltrating cytotoxic immune cells are reprogrammed to regulatory-like/exhausted cells within accepted kidney allografts through a 'defensive tolerance' mechanism. We observed a regulatory B cell (Breg) signature within the accepted kidney. Here we show that despite a Breg phenotype, neither B cell depletion nor the use of μMT recipients which lack B cells, resulted in kidney allograft rejection. Negative regulators of B cell function, and , show increased expression in both accepted kidney and lung allografts. Kidney allografts transplanted in B6. KO recipients underwent antibody mediated rejection. Hypothesizing that similar mechanisms in a tumor microenvironment may attenuate anti-tumor immunity, we observed that expression of , the human homolog of , was associated with resistance to anti-PD1 therapy in human melanomas. In conclusion, B cell expression of FcγRIIB and Siglec-G appear to play an essential role in maintaining transplant tolerance and in tumor evasion of anti-tumor immunity.