Bimodal cell mass distribution separates CD8+ T cells into two distinct types with divergentdifferentiation dynamics

Yu, J.; Zhang, Y.; Duquette, S. M.; Yee, G. L.; Dinter, T.; Usherwood, T. R.; Wu, W.; Miettinen, T.; Spranger, S.; Manalis, S. R.

doi:10.1101/2024.09.26.615179

bioRxiv · 10.1101/2024.09.26.615179

Bimodal cell mass distribution separates CD8+ T cells into two distinct types with divergentdifferentiation dynamics

Yu, J.·Zhang, Y.·Duquette, S. M.·Yee, G. L.·Dinter, T.·Usherwood, T. R.·Wu, W.·Miettinen, T.·Spranger, S.·Manalis, S. R.

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Abstract

T cells are central to immune defense, yet existing molecular and phenotypic assays do not fully capture a cells intrinsic immune potential. Here we show that a single physical property, buoyant mass, reveals hidden heterogeneity within phenotypically similar, resting CD8+ T cells. Using suspended microchannel resonator measurements, we identify two distinct populations: "light" cells, enriched for mitochondrial content but prone to delayed activation and exhaustion, and "heavy" cells, biosynthetically poised for proliferation and memory formation. In patients with melanoma receiving immune checkpoint blockade, pre-treatment buoyant mass profiling of circulating T cells predicted therapeutic response with an accuracy comparable with standard tumor-derived biomarkers. Our findings establish buoyant mass as a label-free, stimulation-independent measure of systemic T cell fitness, providing a rapid and broadly applicable framework for immune profiling and response prediction in cancer and beyond.

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Yu, J., Zhang, Y., Duquette, S. M., Yee, G. L., Dinter, T., Usherwood, T. R., Wu, W., Miettinen, T., Spranger, S., Manalis, S. R.. 2024-09-27. Bimodal cell mass distribution separates CD8+ T cells into two distinct types with divergentdifferentiation dynamics. https://doi.org/10.1101/2024.09.26.615179

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