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

Kelsey B. Bennion, Danya Liu, Abdelhameed S. Dawood, Megan M. Wyatt, Katie L. Alexander, Mohamed S. Abdel-Hakeem, Chrystal M. Paulos and Mandy L. Ford ()
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Kelsey B. Bennion: Emory University School of Medicine
Danya Liu: Emory University School of Medicine
Abdelhameed S. Dawood: Emory University School of Medicine
Megan M. Wyatt: Emory University School of Medicine
Katie L. Alexander: Emory University School of Medicine
Mohamed S. Abdel-Hakeem: Emory University School of Medicine
Chrystal M. Paulos: Emory University School of Medicine
Mandy L. Ford: Emory University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49475-8

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