Regulation of allograft survival by inhibitory FcγRIIb signaling.

Fc gamma receptors (Fc gamma R) provide important immunoregulation. Targeting inhibitory Fc gamma RIIb may therefore prolong allograft survival, but its role in transplantation has not been addressed. Fc gamma RIIb signaling was examined in murine models of acute or chronic cardiac allograft rejection by transplanting recipients that either lacked Fc gamma RIIb expression (Fc gamma RIIb(-/-)) or overexpressed Fc gamma RIIb on B cells (B cell transgenic [BTG]). Acute heart allograft rejection occurred at the same tempo in Fc gamma RIIb(-/-) C57BL16 (B6) recipients as wild type recipients, with similar IgG alloantibody responses. In contrast, chronic rejection of MHC class II mismatched bm12 cardiac allografts was accelerated in Fc gamma RIIb(-/-) mice, with development of more severe transplant arteriopathy and markedly augmented effector autoantibody production. Autoantibody production was inhibited and rejection was delayed in BTG recipients. Similarly, whereas MHC class I mismatched B6.K-d hearts survived indefinitely and remained disease free in B6 mice, much stronger alloantibody responses and progressive graft arteriopathy developed in Fc gamma RIIb(-/-) recipients. Notably, Fc gamma RIIb-mediated inhibition of B6.Kd heart graft rejection was abrogated by increasing T cell help through transfer of additional H2.K-d-specific CD4 T cells. Thus, inhibitory Fc gamma RIIb signaling regulates chronic but not acute rejection, most likely because the supra-optimal helper CD4 T cell response in acute rejection overcomes Fc gamma RIIb-mediated inhibition of the effector B cell population. Immunomodulation of Fc gamma RIIb in clinical transplantation may hold potential for inhibiting progression of transplant arteriopathy and prolonging transplant survival. The Journal of Immunology, 2012, 189: 5694-5702.