*Purpose: To understand the functional role and clinical relevance of FcγRIIB on CD8⁺ T cells in transplantation.

*Methods: See results

*Results: FcγRIIB is the sole inhibitory Fcγ receptor and is known to be expressed on B cells, DCs, and macrophages. We found that CTLA-4Ig-treated FcγRIIB^-/- animals exhibited accelerated graft rejection relative to WT controls (MSTs 20 and 33 d, p=0.0002). Interestingly, this was not associated with enhanced donor-specific antibody, but instead was associated with increased donor-reactive CD8⁺ T cell responses. We then discovered that FcγRIIB is upregulated on a subset of CD44^hiCD62L^lo effector CD8⁺ T cells following transplantation. To determine if FcγRIIB plays a cell-intrinsic role in inhibiting CD8⁺ T cells, we generated a CD8⁺ T cell conditional KO system and observed enhanced accumulation of FcγRIIB^-/- CD8⁺ T cells at 14 (p<0.05) and 21 (p<0.01) d post-transplant relative to WT controls. RNAseq analysis of FACS-sorted, donor-reactive CD8⁺ T cells revealed an enrichment of apoptosis-related genes in FcγRIIB⁺ vs. FcγRIIB^– cells. Mechanistically, FcγRIIB^-/- CD8⁺ cells exhibited lower expression of active caspase 3/7 on day 16 following transplant compared to WT cells (p=0.0315), suggesting that FcγRIIB signals may function intrinsically to induce CD8⁺ T cell apoptosis. To determine if FcγRIIB on donor-reactive CD8⁺ T cells impacted graft rejection, recipients of WT or FcγRIIB^-/- CD8⁺ T cells were treated with anti-CD28 domain antibody. Animals that received FcγRIIB^-/- CD8⁺ cells exhibited accelerated graft rejection following withdrawal from immunosuppression relative to those that received WT CD8⁺ T cells. Given these pre-clinical findings, we then interrogated gene expression profiles in renal transplant recipients enrolled in the CTOT09 study in which patients were weaned from tacrolimus immunosuppression. Compellingly, results indicated that FcγRIIB was one of only 7 genes that were significantly upregulated in PBMC isolated before withdrawal from patients that experienced freedom from rejection following tacrolimus withdrawal vs. those that did not. CellCODE analysis from RNA of patient PBMC revealed tighter associations of FcγRIIB with CD8⁺ T cell transcripts than with B cell, DC, monocyte, CD4⁺ T cell, or NK cell transcripts, indicating that CD8⁺ T cells were most strongly associated with differential expression of FcγRIIB in the stable vs. rejection patients.

*Conclusions: Based on these experiments, we conclude that FcγRIIB is a novel, cell intrinsic CD8⁺ T cell regulatory pathway that could be therapeutically targeted to promote CD8⁺ T cell apoptosis and improve outcomes following transplantation.

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