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A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance
Open accessAbstract
T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for 'self' are either eliminated through TCR-agonist-induced apoptosis (negative selection) or restrained by regulatory T (Treg) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to Treg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells. Although the latter exhibit a restricted TCR repertoire, Treg cells display a highly diverse collection of TCRs. Here we explore in mice whether a specialized mechanism enables agonist-driven selection of Treg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make Treg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables Treg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.
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“Both reparative clusters expressed diagnostic Areg (encoding amphiregulin) and Il1rl1 (specifying the IL-33 receptor, ST2) transcripts and were enriched for an established reparative-Treg signature (SI Appendix, Table S1) (24).”
From Regulatory T cells safeguard liver health during metabolic-associated steatohepatitis (2026) · cites this paper as [24]
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Self-citationRegulatory T cells: mechanisms of differentiation and function
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Self-citationRegulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
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Self-citationA function for interleukin 2 in Foxp3-expressing regulatory T cells
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Self-citationThymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide
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Metadata
- Authors
- Feng, Y., van der Veeken, J., Shugay, M., Putintseva, E. V., Osmanbeyoglu, H. U., Dikiy, S., Hoyos, B. E., Moltedo, B., Hemmers, S., Treuting, P., Leslie, C. S., Chudakov, D. M., & Rudensky, A. Y.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Pirogov Russian National Research Medical University (RU)
- Institute of Bioorganic Chemistry (RU)
- University of Washington (US)
- Corresponding author
- Rudensky, Alexander Y.
- ORCID
- Venue
- Nature
- Published
- 2015-11-25
- Volume
- 528
- Issue
- 7580
- Pages
- 132-136
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4862833
- OpenAlex
- W2174247606
- Cited by
- 157
- References
- 42
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 12 · 2023: 8 · 2022: 13 · 2021: 18 · 2020: 9 · 2019: 21 · 2018: 22 · 2017: 21 · 2016: 14 · 2015: 2
- FWCI
- 9.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research Institute
- Russian Foundation for Basic Research
- National Institutes of Health
- National Human Genome Research Institute (U01HG007893)
- National Cancer Institute (P30CA008748)
- National Institute of Allergy and Infectious Diseases (R37AI034206, R01AI034206)
- 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 › Genomics and Chromatin Dynamics
- Keywords
- regulatory T cells, Foxp3, T cell receptor signaling, self-tolerance, negative selection, epigenetic regulation, thymus
- MeSH terms
- AIRE Protein, Animals, Cell Differentiation, Enhancer Elements, Genetic, Female, Introns, Male, Promoter Regions, Genetic, Receptors, Antigen, T-Cell, Transcription Factors, Receptors, Interleukin-2, Signal Transduction, Conserved Sequence, Self Tolerance, Cell Lineage, Epigenesis, Genetic, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors
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