title: Increased generation of Foxp3(+) regulatory T cells by manipulating antigen presentation in the thymus.
abstract: Regulatory T-cell (Treg) selection in the thymus is essential to prevent autoimmune diseases. Although important rules for Treg selection have been established, there is controversy regarding the degree of self-reactivity displayed by T-cell receptors expressed by Treg cells. In this study we have developed a model of autoimmune skin inflammation, to determine key parameters in the generation of skin-reactive Treg cells in the thymus (tTreg). tTreg development is predominantly AIRE dependent, with an AIRE-independent component. Without the knowledge of antigen recognized by skin-reactive Treg cells, we are able to enhance skin-specific tTreg cell generation using three approaches. First, we increase medullary thymic epithelial cells by using mice lacking osteoprotegerin or by adding TRANCE (RANKL, Tnfsf11). Second, we inject intrathymically peripheral dendritic cells from skin-draining sites. Finally, we inject skin tissue lysates intrathymically. These findings have implications for enhancing the generation of organ-specific Treg cells in autoimmune diseases.
authors.affiliation: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.|The Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Jiqiang
authors.initials: J
authors.lastname: Lin
authors.affiliation: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.|The Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.
authors.forename: Hernandez Moura
authors.initials: HM
authors.lastname: Silva
authors.affiliation: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.
authors.forename: Alissa
authors.initials: A
authors.lastname: Trzeciak
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.|Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Schwab
authors.affiliation: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.|Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.|Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.affiliation: Molecular Pathogenesis Program, Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.|Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lafaille
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D002678:Chimera; D003713:Dendritic Cells / Q000276:immunology; D003872:Dermatitis / Q000276:immunology*; D020405:Dermis / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D053244:Osteoprotegerin / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology; D000096927:AIRE Protein
chemical_list: D051858:Forkhead Transcription Factors; D053244:Osteoprotegerin; D053245:RANK Ligand; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D000096927:AIRE Protein; C498833:Foxp3 protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse