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Bennion, Kelsey B; Liu, Danya; Dawood, Abdelhameed S; Wyatt, Megan M; Alexander, Katie L; Abdel-Hakeem, Mohamed S; Paulos, Chrystal M; d, Mandy L
Nature communications, 06/2024, Volume: 15, Issue: 1Journal Article
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 FcγRIIB 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.
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