Single-Cell Transcriptomics of Regulatory T Cells Reveals Trajectories of Tissue Adaptation

Summary

Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4 ⁺ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.

Graphical Abstract

Highlights

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  scRNA-seq reveals Treg cell tissue-specific signatures

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  The phenotype of Treg cells shows progressive adaptation to barrier tissues

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  Treg cells share transcriptional dynamics of adaptation to colon and skin

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  Modules of peripheral Treg cell identity are conserved between mouse and human

Abstract

Treg cells are known to display tissue-specific heterogeneity. Miragaia and colleagues probe Treg cells in lymphoid and barrier tissues by single-cell transcriptomics. They show that Treg cells segregate into subpopulations along a continuum of tissue adaptation and present conserved expression programs between homeostasis and disease and mouse and human.