Fc receptors are expressed by many types of immune cells and bind to the constant portion of immunoglobulin to mediate their effector functions. The inhibitory receptor FcγRIIB is an important negative regulator of humoral and cellular immune responses. Previous studies by our group revealed that FcγRIIB-/- (KO) mice are resistant to the ability of CTLA4-Ig to prolong graft survival in a minor mismatch (OVA) model of skin transplantation. Here, we investigate the mechanisms underlying this resistance. Interestingly, enhanced humoral responses in KO mice were not responsible for the CTLA4-Ig-resistant rejection, as we observed that CTLA4-Ig treatment was able to inhibit graft-specific antibody formation in both WT and KO mice, indicating that a different mechanism may be responsible for the accelerated rejection seen in KO animals.

Given the interplay between T and B cells during alloreactive responses and the rise in the use of monoclonal antibody therapy to control T cell alloreactivity, we sought to investigate the role that FcγRIIB may play in T cell-mediated graft rejection. While T cells have long been thought to not express Fc receptors, we observed the expression of FcγRIIB on allospecific CD4 and CD8 effector T cells by day 14 following skin transplantation (61.5% and 64.4%, respectively), and this expression was maintained at a high level on memory T cells. Furthermore, we showed that most allospecific cells capable of making TNF and IFNγ in response to ex vivo restimulation also coexpressed FcγRIIB (88.3%).

With this novel finding of high FcγRIIB expression on donor-reactive memory T cells and the fact that memory T cells are a significant barrier to transplantation, we sought to determine if FcγRIIB functionally impacts recall responses to a graft. We transferred OVA-specific CD4 and CD8 T cells to B6 mice and allowed them to fully reject mOVA skin grafts. At a memory timepoint, these mice were given a second mOVA graft, and recipients were either left untreated or treated with the FcγRIIB-blocking 2.4G2 antibody. We observed a greater expansion of CD8 T cells in the draining lymph node of 2.4G2-treated animals, suggesting that FcγRIIB plays a significant functional role in the control of secondary donor-reactive CD8 T cell expansion in this model. Taken together, these data identify FcγRIIB as a novel coinhibitory pathway regulating donor-reactive memory CD8 T cell responses in the setting of transplantation.

CITATION INFORMATION: Pinelli D, Wagener M, Liu D, Badell I, Ford M. Inhibitory FcγRIIB Functionally Inhibits Donor-Reactive CD8⁺ Memory T Cell Responses Following Transplantation. Am J Transplant. 2016;16 (suppl 3).

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