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.
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Joris
authors.initials: J
authors.lastname: van der Veeken
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Miklukho-Maklaya 16/10, Moscow, Russia.|Pirogov Russian National Research Medical University, 117997, Ostrovityanova 1, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Shugay
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Miklukho-Maklaya 16/10, Moscow, Russia.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Putintseva
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Hatice U
authors.initials: HU
authors.lastname: Osmanbeyoglu
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Dikiy
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Beatrice E
authors.initials: BE
authors.lastname: Hoyos
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Bruno
authors.initials: B
authors.lastname: Moltedo
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Saskia
authors.initials: S
authors.lastname: Hemmers
authors.affiliation: Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Piper
authors.initials: P
authors.lastname: Treuting
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Leslie
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997, Miklukho-Maklaya 16/10, Moscow, Russia.|Pirogov Russian National Research Medical University, 117997, Ostrovityanova 1, Moscow, Russia.
authors.forename: Dmitriy M
authors.initials: DM
authors.lastname: Chudakov
authors.affiliation: Howard Hughes Medical Institute and Immunology Program, Ludwig Center at Memorial Sloan-Kettering Cancer Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D017124:Conserved Sequence / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D007438:Introns / Q000235:genetics; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency; D000096927:AIRE Protein
chemical_list: D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; D000096927:AIRE Protein; C498833:Foxp3 protein, mouse