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, Siglecg and Fcgr2b, show increased expression in both accepted kidney and lung allografts. Kidney allografts transplanted in B6.Fcgr2b KO recipients underwent antibody mediated rejection. Hypothesizing that similar mechanisms in a tumor microenvironment may attenuate anti-tumor immunity, we observed that expression of SIGLEC10, the human homolog of Siglecg, 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.