title: Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus.
abstract: The contribution of thymic antigen-presenting-cell (APC) subsets in selecting a self-tolerant T cell population remains unclear. We show that bone marrow (BM) APCs and medullary thymic epithelial cells (mTECs) played nonoverlapping roles in shaping the T cell receptor (TCR) repertoire by deletion and regulatory T (Treg) cell selection of distinct TCRs. Aire, which induces tissue-specific antigen expression in mTECs, affected the TCR repertoire in a manner distinct from mTEC presentation. Approximately half of Aire-dependent deletion or Treg cell selection utilized a pathway dependent on antigen presentation by BM APCs. Batf3-dependent CD8α⁺ dendritic cells (DCs) were the crucial BM APCs for Treg cell selection via this pathway, showing enhanced ability to present antigens from stromal cells. These results demonstrate the division of function between thymic APCs in shaping the self-tolerant TCR repertoire and reveal an unappreciated cooperation between mTECs and CD8α⁺ DCs for presentation of Aire-induced self-antigens to developing thymocytes.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Justin S A
authors.initials: JSA
authors.lastname: Perry
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Chan-Wang J
authors.initials: CJ
authors.lastname: Lio
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kau
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Nutsch
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Gordon
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: chsieh@wustl.edu.
authors.forename: Chyi-Song
authors.initials: CS
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D001854:Bone Marrow Cells / Q000276:immunology*; D016827:CD8 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics; D017634:Self Tolerance / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D050976:Basic-Leucine Zipper Transcription Factors; D016827:CD8 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D012097:Repressor Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C431698:CD8alpha antigen; C533289:SNFT protein, mouse