Morris et al. showed that mice deficient in inhibitory Fcγ receptor (FcγR)IIB or receiving FcγRIIB-/- T cells vs. wildtype (wt) more quickly rejected melanoma and/or skin allografts. Survival of FcγRIIB-/ - (but not wt) differentiated EomesloCD62LloCD8+ effector T cells was enhanced, and blocking FcγRIIB boosted CD44hiCD62LloCD8+ T cell accretion and responses in vivo. FcγRIIB, on cytokine producing CD8+ T cells after multiple divisions, bound Fgl2 to signal caspase-3/7-mediated apoptosis. Increased human CD8+ T cell FcγRIIB expression correlated with being rejection-free after Tacrolimus withdrawal in a small clinical trial of renal transplant recipients.
Contributed by Paula Hochman
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 FcgammaRIIB 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 FcgammaRIIB-mediated control of CD8(+) T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcgammaRIIB on CD8(+) T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b(+), but not Fcgr2b(-/-), CD8(+) T cells. Increased expression of FcgammaRIIB 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 FcgammaRIIB in regulating CD8(+) T cell immunity.
Author Info: (1) Department of Surgery, Emory University, Atlanta, GA, USA. (2) Department of Surgery, Emory University, Atlanta, GA, USA. (3) Department of Surgery, Emory University, Atlanta,
Author Info: (1) Department of Surgery, Emory University, Atlanta, GA, USA. (2) Department of Surgery, Emory University, Atlanta, GA, USA. (3) Department of Surgery, Emory University, Atlanta, GA, USA. (4) Department of Surgery, Emory University, Atlanta, GA, USA. (5) Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK. (6) Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA. (7) Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA. (8) Translational Transplant Research Center and the Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (9) Translational Transplant Research Center and the Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (10) Translational Transplant Research Center and the Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (11) Department of Surgery, Emory University, Atlanta, GA, USA. Electronic address: mandy.ford@emory.edu.
