Bimodal cell mass distribution separates CD8+ T cells into two distinct types with divergent differentiation dynamics
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T cell heterogeneity is a cornerstone of the adaptive immune response, with CD8+ T cells playing a pivotal role in mediating cytotoxic responses to pathogens and tumors. While traditional studies have focused on phenotypic and functional diversity through surface marker expression and functional assays, the significance of biophysical properties in delineating T cell subpopulations remains underexplored. Here, we show that resting T cells exhibit a bimodal distribution in buoyant mass, which is not captured by surface marker based canonical immunophenotypes or physical parameters such as volume, density, dry mass, or light scattering. Functionally, we demonstrate that T cells with lower buoyant mass exhibit reduced proliferation, tend towards effector differentiation, and become more exhausted in the presence of innate tumor-secreted factors. Conversely, T cells with higher buoyant mass show greater memory potential and resistance to exhaustion. Our study not only provides insights into T cell biology but also suggests buoyant mass as a promising label-free biomarker to potentiate T cell-based therapies.
