IFNγ expression correlates with enhanced cytotoxicity in CD8 + T cells
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Background
CD8+ T lymphocytes (CTLs) act as serial killers of infected or malignant cells by releasing large amounts of interferon-gamma (IFNγ) and granzymes. Although IFNγ is a pleiotropic cytokine with diverse immunomodulatory functions, its precise spatiotemporal regulation and role in CTL-mediated cytotoxicity remain incompletely characterized.
Methods
Using wild-type (WT) and granzyme B-mTFP knock-in mice, we combined in vitro approaches, including T-cell isolation and culture, plate-bound anti-CD3e stimulation, degranulation assays, flow cytometry, immunofluorescence, and structured illumination microscopy, to investigate IFNγ dynamics in CTLs.
Results
IFNγ expression in CTLs was rapid, transient, and strictly dependent on T-cell receptor (TCR) activation. We identified two functionally distinct IFNγ-producing subsets: IFNγ high (IFNγ hi ) and IFNγ low (IFNγ lo ) CTLs. IFNγ hi CTLs exhibited an effector/effector memory phenotype, significantly elevated CD107a surface expression (a marker of lytic granule exocytosis), and pronounced colocalization with cis-Golgi and granzyme B compared to IFNγ lo CTLs. Furthermore, CRTAM, an early activation marker, correlated with IFNγ expression in naive CTLs.
Conclusion
Our findings establish a link between elevated IFNγ production and enhanced CTL cytotoxicity, implicating CRTAM as a potential regulator of early CTL activation and IFNγ induction. These insights provide a foundation for optimizing T cell-based immunotherapies against infections and cancers.
