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 Treg clusters express Areg and Il1rl1 and are enriched for an established reparative-Treg signature.
“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]
The Methods section on RNA sequencing describes signatures of TCR-dependent genes in Treg cells, not a reparative-Treg signature. Searches for Areg, Il1rl1, amphiregulin, ST2, and reparative Treg cells found no passage in our copy addressing the claimed markers or enrichment of the two clusters. No page number is available for these passages. (LLM, conf=0.76)
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- 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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