CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner

The regulatory circuits dictating CD8+ T cell responsiveness vs. 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 from antigen-specific CD8+ T cells prolonged CD8+ T cell persistence, decreased phenotypic and transcriptomic signatures of T cell exhaustion, and improved tumor control. Melanoma patients who died of their disease exhibited increased expression of Fgl2 in tumor-infiltrating CD8+ T cells as compared to those who survived. PD-1+CD8+ T cell-derived Fgl2 also negatively regulated virus-specific T cell responses in a model of chronic viral infection. Mechanistically, the enhanced responsiveness of Fgl2-deficient CD8+ T cells is underpinned by the interaction of Fgl2 with CD8+ T cell-expressed FcγRIIB, ligation of which results in caspase 3/7-mediated apoptosis. These data illuminate a novel cell-autonomous regulatory axis by which PD-1+ CD8+ T cell responses are regulated in vivo. WT or Fgl2-/- OT-I tumor-specific CD8+ T cells were given to mice a day prior to B16-OVA challenge. On day 14 post tumor challenge, the spleens of the mice were harvested, and OT-I T cells were isolated by sorting on CD3+CD8+Thy1.1+ (congenic marker) for subsequent bulk RNA-sequencing Emory NPRC Genomics Core (contributor)