Signaling through the Inhibitory Fc Receptor FcγRIIB Induces CD8 + T Cell Apoptosis to Limit T Cell Immunity

Immunity. 2020 Jan 14;52(1):136-150.e6. doi: 10.1016/j.immuni.2019.12.006.

Abstract

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 FcγRIIB 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 FcγRIIB-mediated control of CD8+ T cell immunity, and instead, the immunosuppressive cytokine fibrinogen-like 2 (Fgl2) was a functional ligand for FcγRIIB on CD8+ T cells. Fgl2 induced caspase-3/7-mediated apoptosis in Fcgr2b+, but not Fcgr2b-/-, CD8+ T cells. Increased expression of FcγRIIB 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 FcγRIIB in regulating CD8+ T cell immunity.

Keywords: CD8(+) T cells; FcgRIIB; Fgl2; apoptosis; transplantation; tumor immunology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Caspase 3 / immunology
  • Caspase 7 / immunology
  • Cell Line, Tumor
  • Female
  • Fibrinogen / genetics
  • Fibrinogen / immunology*
  • Graft Rejection / immunology
  • Humans
  • Immunoglobulin G / immunology
  • Immunosuppression Therapy
  • Male
  • Melanoma, Experimental
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology*
  • Young Adult

Substances

  • FCGR2B protein, human
  • FGL2 protein, human
  • Immunoglobulin G
  • Receptors, IgG
  • Fibrinogen
  • CASP3 protein, human
  • CASP7 protein, human
  • Caspase 3
  • Caspase 7