CD8+ T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB.
Nat Commun
; 15(1): 5280, 2024 Jun 20.
Article
em En
| MEDLINE
| ID: mdl-38902261
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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Base de dados:
MEDLINE
Assunto principal:
Receptores de IgG
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Linfócitos T CD8-Positivos
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Receptor de Morte Celular Programada 1
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Melanoma
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Camundongos Endogâmicos C57BL
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article