title: Thymic B Cells Are Licensed to Present Self Antigens for Central T Cell Tolerance Induction.
abstract: Thymic antigen-presenting cells (APCs) such as dendritic cells and medullary thymic epithelial cells (mTECs) use distinct strategies of self-antigen expression and presentation to mediate central tolerance. The thymus also harbors B cells; whether they also display unique tolerogenic features and how they genealogically relate to peripheral B cells is unclear. Here, we found that Aire is expressed in thymic but not peripheral B cells. Aire expression in thymic B cells coincided with major histocompatibility class II (MHCII) and CD80 upregulation and immunoglobulin class-switching. These features were recapitulated upon immigration of naive peripheral B cells into the thymus, whereby this intrathymic licensing required CD40 signaling in the context of cognate interactions with autoreactive CD4(+) thymocytes. Moreover, a licensing-dependent neo-antigen selectively upregulated in immigrating B cells mediated negative selection through direct presentation. Thus, autoreactivity within the nascent T cell repertoire fuels a feed forward loop that endows thymic B cells with tolerogenic features.
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 Munich, Germany.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Yamano
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 Munich, Germany.
authors.forename: Jelena
authors.initials: J
authors.lastname: Nedjic
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 Munich, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Hinterberger
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 Munich, Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Steinert
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Koser
authors.affiliation: Division of Developmental Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Sheena
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Gerdes
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany; Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 Amsterdam, the Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Lutgens
authors.affiliation: Department of Oral Molecular Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto, Tokushima 770-8504, Japan.
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Division of Developmental Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Kyewski
authors.affiliation: Institute for Immunology, Ludwig-Maximilians-University Munich, Goethestrasse 31, 80336 Munich, Germany. Electronic address: ludger.klein@med.lmu.de.
authors.forename: Ludger
authors.initials: L
authors.lastname: Klein
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D061167:Central Tolerance / Q000235:genetics; D060966:Clonal Selection, Antigen-Mediated / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015398:Signal Transduction; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D018122:B7-1 Antigen; D019013:CD40 Antigens; D000949:Histocompatibility Antigens Class II; D014157:Transcription Factors; D000096927:AIRE Protein