Authors
Plotkin, A. L., Mullins, G. N., Green, W. D., Shi, H., Chung, H. K., Yi, H., Stanley, N., Milner, J. J.
Abstract
Immune responses evolve across time and tissues through coordinated programs of proliferation, differentiation, and migration, yet most single-cell measurements capture only static molecular snapshots. As a result, reconstructing how immune cells transition between alternative fates remains challenging, particularly for CD8 T cells, whose differentiation is highly dynamic and shaped by rapid expansion, contraction, and tissue trafficking. Here, we introduce an optimal transport-based fate mapping framework that reconstructs continuous CD8 T cell trajectories across time and tissues. Applied to longitudinal single-cell RNA-seq data from CD8 T cells responding to acute viral infection in mice, this approach accurately recapitulates population dynamics and resolves coherent effector and memory T cell differentiation trajectories. Extending the model to multiple tissues, we identify and experimentally validate temporally distinct waves of migration into the small intestine that give rise to divergent tissue-resident memory (Trm) fates, long-lived T cells crucial in immunosurveillance. By integrating optimal transport inference with time-resolved in vivo labeling, we demonstrate that CD52 marks recent tissue entrants and distinguishes them from Trm precursors. Finally, trajectory-guided analysis of transcription factor regulons reveals both shared and context-specific gene regulatory programs and identifies AP4 as a key regulator of circulating versus tissue-resident specification. Together, these results establish optimal transport as a principled framework for reconstructing immune cell fate dynamics and provide a quantitative map of early events governing antiviral CD8 T cell differentiation across tissues.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 27 Feb 2026.
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