Bennion et al. showed that exhausted antigen-specific PD-1+TCF-1− CD8+ T cells secreted the immunoregulatory cytokine fibrinogen-like protein 2 (Fgl2), which regulated CD8+ T cell responses against tumors and viruses in a cell-autonomous manner. Cell-intrinsic interaction of Fgl2 with FcγRIIB on CD8+ T cells led to caspase 3/7-mediated deletion of antigen-specific CD8+ T cells. KO of Fgl2 from antigen-specific CD8+ T cells increased FcγRIIB+ CD8+ T cells persistence and improved responses against cancer and chronic viral infection. Higher expression of FcγRIIB and Fgl2 on CD8+ T cells was associated with poorer survival in melanoma patients.
Contributed by Shishir Pant
ABSTRACT: The regulatory circuits dictating CD8(+) T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating antigen-specific PD-1(+) TCF-1(-) CD8(+) T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8(+) T cells prolongs CD8(+) T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1(+) CD8(+) T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8(+) T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2-expressing CD8(+) T cells, when compared to Fgl2-deficient CD8(+) T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8(+) T cell-expressed Fc_RIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1(+) CD8(+) T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity.
Author Info: (1) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Emory Winship Cancer Institute, Atlanta, GA, USA. Cancer Biology PhD Program, Emory University, At
Author Info: (1) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Emory Winship Cancer Institute, Atlanta, GA, USA. Cancer Biology PhD Program, Emory University, Atlanta, GA, USA. (2) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. (3) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. (4) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Emory Winship Cancer Institute, Atlanta, GA, USA. Cancer Biology PhD Program, Emory University, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA. (5) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Immunology and Molecular Pathogenesis PhD Program, Emory University, Atlanta, GA, USA. (6) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. (7) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Emory Winship Cancer Institute, Atlanta, GA, USA. Cancer Biology PhD Program, Emory University, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA. (8) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. mandy.ford@emory.edu. Emory Winship Cancer Institute, Atlanta, GA, USA. mandy.ford@emory.edu. Cancer Biology PhD Program, Emory University, Atlanta, GA, USA. mandy.ford@emory.edu. Immunology and Molecular Pathogenesis PhD Program, Emory University, Atlanta, GA, USA. mandy.ford@emory.edu.
