Seminal studies in mouse models and emerging data in NHP and patient populations have consistently implicated memory T cells as being a formidable barrier to long-term, rejection-free allograft survival, particularly in the setting of costimulation blockade. As such, work in our laboratory over the past several years has focused on identifying new pathways that control memory T cell responses during transplantation. FcγRIIB, the only inhibitory Fc receptor, inhibits intracellular signaling via the ITIM motif located in its cytoplasmic region. FcγRIIB is known to be expressed by many immune cell types, including B cells, DCs, macrophages and granulocytes; however, the general consensus for the past few decades has been that T cells do not express this molecule. Work done in the last cycle of the grant published by our lab indicated that FcγRIIB-/- mice exhibit increased costimulation blockade-resistant rejection relative to WT controls. This increased rejection was not the result of increased antibody secretion, as no differences in anti-donor antibodies were detected in these animals. Instead, we discovered that FcγRIIB is expressed on a subset of memory CD8+ T cells generated via both transplantation and virally-elicited heterologous immunity, and that blockade of this novel coinhibitory pathway results in enhanced donor-reactive memory CD8+ T cell responses. Our data thus suggest a previously unidentified functional role for FcγRIIB coinhibitory signaling in regulating CD8+ memory T cells during transplantation. However, the mechanisms underlying this observation, including the identity of the FcγRIIB ligand in this system (i.e. endogenous antibody vs. Fc-containing biologic), remain unknown. Compellingly, our new preliminary data reveal that the degree of expression of FcγRIIB on donor- reactive CD8+ memory T cell populations directly correlated with susceptibility of those cells to costimulation blockade, providing further evidence for a T cell-intrinsic role for FcγRIIB coinhibitory signaling in transplantation. Overall, these data suggest a novel mechanism by which the production of alloantibody may function as a negative feedback loop to prevent alloreactive CD8+ T cell activation, and raise the possibility of an innovative new approach to controlling donor-reactive CD8+ memory T cells during transplantation. Thus, in this proposal we aim to further interrogate the mechanisms by which FcγRIIB inhibitory signaling regulates donor-reactive memory CD8+ T cell responses in transplantation by determining the T cell intrinsic role of FcγRIIB signaling, identifying the FcγRIIB ligand in this system (endogenous antibody/immune complexes vs. Fc-containing biologics), and interrogating the epigenetic and transcription-factor mediated control of FcγRIIB expression on donor-reactive CD8+ memory T cells during transplantation.