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Nat Immunol. 2018 Mar;19(3):291-301. doi: 10.1038/s41590-018-0051-0. Epub 2018 Feb 12.

Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR.

Author information

1
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
2
Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
3
Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
4
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. dm@hms.harvard.edu.
5
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. cbdm@hms.harvard.edu.

Abstract

CD4+ T regulatory cells (Treg) are central to immune homeostasis, their phenotypic heterogeneity reflecting the diverse environments and target cells that they regulate. To understand this heterogeneity, we combined single-cell RNA-seq, activation reporter and T cell receptor (TCR) analysis to profile thousands of Treg or conventional CD4+FoxP3- T cells (Tconv) from mouse lymphoid organs and human blood. Treg and Tconv pools showed areas of overlap, as resting 'furtive' Tregs with overall similarity to Tconvs or as a convergence of activated states. All Tregs expressed a small core of FoxP3-dependent transcripts, onto which additional programs were added less uniformly. Among suppressive functions, Il2ra and Ctla4 were quasiconstant, inhibitory cytokines being more sparsely distributed. TCR signal intensity did not affect resting/activated Treg proportions but molded activated Treg programs. The main lines of Treg heterogeneity in mice were strikingly conserved in human blood. These results reveal unexpected TCR-shaped states of activation, providing a framework to synthesize previous observations of Treg heterogeneity.

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