| First Author | Bennion KB | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 5280 |
| PubMed ID | 38902261 | Mgi Jnum | J:350075 |
| Mgi Id | MGI:7661854 | Doi | 10.1038/s41467-024-49475-8 |
| Citation | Bennion KB, et al. (2024) CD8(+) T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcgammaRIIB. Nat Commun 15(1):5280 |
| abstractText | 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 FcgammaRIIB 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. |
