Effector CD8 + T cells are important mediators of adaptive immunity, and receptor-ligand interactions that regulate their survival may have therapeutic potential. Here, we identified a subset of effector CD8 + T cells that expressed the inhibitory fragment crystallizable (Fc) receptor FcgRIIB following activation and multiple rounds of division. CD8 + T cell-intrinsic genetic deletion of Fcgr2b increased CD8 + effector T cell accumulation, resulting in accelerated graft rejection and decreased tumor volume in mouse models. Immunoglobulin G (IgG) antibody was not required for FcgRIIB-mediated control of CD8 + T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcgRIIB on CD8 + T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b + , but not Fcgr2b À/À , CD8 + T cells. Increased expression of FcgRIIB correlated with freedom from rejection following withdrawal from immunosuppression in a clinical trial of kidney transplant recipients. Together, these findings demonstrate a cell-intrinsic coinhibitory function of FcgRIIB in regulating CD8 + T cell immunity.

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In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8 + T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8 + T cells in an experimental melanoma model and expressed on CD8 + T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8 + T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b –/– tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8 + T cells with greater effector function. Finally, FcγRIIB was expressed on CD8 + memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8 + T cells.

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Survivorship practitioners should have heightened awareness for rehabilitation intervention in patients with greater axillary surgery and burden of disease. Patients with more activity restriction and lower levels of function in the early postoperative period may benefit from rehabilitation intervention. Future studies should focus on implementing a screening tool to identify patients in need of rehabilitation referral.