A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance Journal Article
| 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. |
| Article Title: | A mechanism for expansion of regulatory T-cell repertoire and its role in self-tolerance |
| Abstract: | 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. © 2015 Macmillan Publishers Limited. All rights reserved. |
| Keywords: | signal transduction; controlled study; promoter region; nonhuman; transcription factor foxp3; cd8+ t lymphocyte; animal cell; mouse; mus; interleukin 13; cell differentiation; wild type; b lymphocyte; cell lineage; t lymphocyte receptor; immunological tolerance; regulatory t lymphocyte; gamma interferon; cd4+ t lymphocyte; cytokine production; autoimmunity; cytotoxic t lymphocyte antigen 4; thymocyte; cell expansion; enhancer region; histone acetylation; high throughput sequencing; male; female; priority journal; article; t cell culture |
| Journal Title: | Nature |
| Volume: | 528 |
| Issue: | 7580 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-12-03 |
| Start Page: | 132 |
| End Page: | 136 |
| Language: | English |
| DOI: | 10.1038/nature16141 |
| PROVIDER: | scopus |
| PUBMED: | 26605529 |
| PMCID: | PMC4862833 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 7 January 2016 -- 132 -- Source: Scopus |
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