Abstract
SummaryNon-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.
Highlights
Regulatory T (Treg) cells are a specialized CD4+ T cell subset that controls immune responses and play a central role in homeostasis (Sakaguchi 2004; Izcue, Coombes, and Powrie 2009)
Our results show that these steady-state adaptations share a core signature between bLN-to-skin and mLN-to-colon trajectories, indicative of a general Non-lymphoid tissues (NLTs) residency program in barrier tissues
Treg and Tmem Cell Identity in NLTs Is Driven by a Common Expression Module We performed scRNA-seq on isolated CD4+Foxp3+ (Treg) and CD4+Foxp3-CD44high memory (Tmem) T cells (Figure S1A) from two barrier NLT sites—the colonic lamina propria and the skin—their lymphoid counterparts in the draining mesenteric and brachial lymph nodes, and the spleen from a Foxp3-GFP mouse reporter line (Bettelli et al, 2006) (Figure 1A)
Summary
Regulatory T (Treg) cells are a specialized CD4+ T cell subset that controls immune responses and play a central role in homeostasis (Sakaguchi 2004; Izcue, Coombes, and Powrie 2009). Recent studies have described unique tissue-specific adaptations of non-lymphoid tissue (NLTs) Treg cells distinct from their lymphoid tissue (LT) counterparts This includes acquisition of an effector phenotype with expression of transcripts encoding effector molecules (Ctla, Gzmb, Klrg1), chemokines and their receptors (Ccr4), and immunosuppressive cytokines (Il10) (Panduro, Benoist, and Mathis 2016; Bollrath and Powrie 2013), in addition to tissue-specific signature genes associated with their role in each environment (Liston and Gray 2014). Their full transcriptional phenotype and its reflection on NLT population heterogeneity is yet to be uncovered. Treg cell migration requires tissue-specific cues involving integrins, chemokine, and other G-protein coupled receptors (Cepek et al, 1994; Kim et al, 2013; Chow, Banerjee, and Hickey 2015)
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