*Purpose: Donor-reactive memory T cells represent a potent immunologic barrier to long-term graft survival and tolerance induction. To identify novel pathways that regulate memory T cell function following transplantation, we conducted high-dimensional immunophenotypic analysis of CD8⁺ memory T cell populations that were either susceptible or resistant to immunosuppression.

*Methods: See Results

*Results: Our results identified expression of a novel T cell coinhibitory molecule expressed on CD8⁺ memory T cells that was highly prevalent in susceptible memory T cell populations (55%) but less prevalent in resistant memory CD8⁺ T cell populations (22%). FcγRIIB is an inhibitory Fc receptor that was previously only known to be expressed on B cells and innate immune cells. Our data now demonstrate that FcγRIIB is expressed on CD44^hi CD8⁺ T cells during alloimmunity, and that the degree of expression of FcγRIIB on memory CD8⁺ T cells positively correlated (r²=0.9943) with the median survival time (MST) following skin transplantation and treatment with costimulation blockade. To determine whether FcγRIIB functionally regulates memory CD8⁺ T cell responses during transplantation, we generated conditional knockouts of FcγRIIB on graft-specific CD8⁺ T cells. Importantly, recipients containing FcγRIIB^-/- memory CD8⁺ T cells exhibited accelerated allograft rejection relative to those containing WT memory CD8⁺ T cells following transplantation in the context of costimulation blockade (MST 92 vs. undefined). Mechanistically, ligation of FcγRIIB on CD8⁺ T cells with the immunosuppressive molecule Fgl2 induced activation of caspase 3/7 (p<0.01), demonstrating that FcγRIIB signaling via Fgl2 is a novel pathway that induces apoptosis in pathologic memory CD8⁺ T cells during transplantation. We next queried the relationship between T cell expression of FcγRIIB and risk of rejection in human renal transplant recipients taking part in the CTOT-09 trial. Transcript analysis of pre-withdrawal PBMC revealed that FCGR2B was significantly higher in patients who were rejection-free off tacrolimus immunosuppression as compared to those who developed rejection. Bioinformatic analysis using the CellCODE platform indicated that the difference in FCGR2B expression observed between stable vs. rejected patients were driven by changes in CD8⁺ T cells.

*Conclusions: These data in mouse and man demonstrate that FcγRIIB is a potent negative regulator of memory CD8⁺ T cell responses during alloimmunity, and suggest that therapeutic targeting of this pathway could be used to improve transplant outcomes in sensitized individuals.

« Back to 2020 American Transplant Congress