Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR
Open accessAbstract
CD4+ T regulatory cells (T reg) 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 T reg or conventional CD4+FoxP3- T cells (T conv) from mouse lymphoid organs and human blood. T reg and T conv pools showed areas of overlap, as resting 'furtive' T regs with overall similarity to T convs or as a convergence of activated states. All T regs 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 T reg proportions but molded activated T reg programs. The main lines of T reg 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 T reg heterogeneity.
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The aTregs subset overexpressed Foxp3, Cd81, Cd74, and Cst7, together with aTregs-associated genes Tnfrsf4, Tnfrsf9, Tnfrsf18, and Ikzf2.
“activated regulatory T cells (aTregs) overexpressing Foxp3, Cd81, Cd74, and Cst7 genes, together with aTregs-associated genes such as Tnfrsf4, Tnfrsf9, Tnfrsf18, and Ikzf2 (21, 29, 30)”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [21]
Genes up-regulated in old cells presented a mix of inflammatory (e.g., S100a4, S100a11, Ccl5) and regulatory (e.g., Maf, Ikzf2, Tnfrsf4) signatures, as well as exhaustion markers (e.g., Lag3, Tnfsf8).
“genes up-regulated in old cells presented a mix of inflammatory (e.g., S100a4, S100a11, and Ccl5 genes) and regulatory (e.g., Maf, Ikzf2, and Tnfrsf4 genes) signatures (21), as well as exhaustion markers [e.g., Lag3 and Tnfsf8 genes (22); Fig. 1E and Materials and Methods].”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [21]
CD81 was coexpressed with PD1, TNFRSF4, TNFRSF9, Helios, IL1R2, and LAG3, affirming the activated phenotype of aTregs.
“CD81 was coexpressed with PD1, TNFRSF4, TNFRSF9, Helios, IL1R2, and LAG3, which together affirmed the activated phenotype of aTregs [Fig. 3, E and F; (21)].”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [21]
The TME comprises a large CAF population with subsets of fibroblasts of diverse phenotypes.
“In addition to immune cells, the TME comprises a large CAF population with subsets of fibroblasts of diverse phenotypes77,222–226.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [224]
Activated fibroblasts and myofibroblasts abundantly secrete various ECM proteins, and matrix metalloproteases, cathepsins and other ECM remodeling enzymes.
“Indeed, activated fibroblasts and myofibroblasts abundantly secrete various ECM proteins, and matrix metalloproteases, cathepsins and other ECM remodeling enzymes77,224,235,236.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [224]
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- Authors
- Zemmour, D., Zilionis, R., Kiner, E., Klein, A. M., Mathis, D., & Benoist, C.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Mathis, Diane
- Benoist, Christophe
- Venue
- Nature Immunology
- Published
- 2018-02-12
- Volume
- 19
- Issue
- 3
- Pages
- 291-301
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC6069633
- OpenAlex
- W2793411374
- Cited by
- 384
- References
- 91
- Citations by year
- 2026: 22 · 2025: 32 · 2024: 34 · 2023: 41 · 2022: 53 · 2021: 72 · 2020: 60 · 2019: 51 · 2018: 17 · 2017: 2
- FWCI
- 21.70
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-05-03)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI051530, R01AI116834, R01AI125603, R37AI051530)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- regulatory T cells, T cell receptor signaling, Treg heterogeneity, Foxp3, transcriptional programs, suppressive function, Treg activation, conventional CD4+ T cells, IL2RA, CTLA-4, immune homeostasis, single-cell RNA sequencing
- MeSH terms
- Animals, Humans, Lymphocyte Activation, Phenotype, Receptors, Antigen, T-Cell, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory, Mice, Transcriptome
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