CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB

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 gamma 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.