title: NF-κB-inducing kinase in thymic stroma establishes central tolerance by orchestrating cross-talk with not only thymocytes but also dendritic cells.
abstract: Essential roles of NF-κB-inducing kinase (NIK) for the development of medullary thymic epithelial cells (mTECs) and regulatory T cells have been highlighted by studies using a strain of mouse bearing a natural mutation of the NIK gene (aly mice). However, the exact mechanisms underlying the defect in thymic cross-talk leading to the breakdown of self-tolerance in aly mice remain elusive. In this study, we demonstrated that production of regulatory T cells and the final maturation process of positively selected conventional αβ T cells are impaired in aly mice, partly because of a lack of mature mTECs. Of note, numbers of thymic dendritic cells and their expression of costimulatory molecules were also affected in aly mice in a thymic stroma-dependent manner. The results suggest a pivotal role of NIK in the thymic stroma in establishing self-tolerance by orchestrating cross-talk between mTECs and dendritic cells as well as thymocytes. In addition, we showed that negative selection was impaired in aly mice as a result of the stromal defect, which accounts for the development of organ-specific autoimmunity through a lack of normal NIK.
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan; and.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mouri
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan; and.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishijima
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawano
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan; and.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Hirota
authors.affiliation: Department of Immunology, Graduate School of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakaguchi
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan; and.
authors.forename: Junko
authors.initials: J
authors.lastname: Morimoto
authors.affiliation: Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan; and mitsuru@ier.tokushima-u.ac.jp.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D017634:Self Tolerance / Q000276:immunology*; D017154:Stromal Cells / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D060168:Thymocytes / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D018122:B7-1 Antigen; D017346:Protein Serine-Threonine Kinases; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000097782:NF-kappaB-Inducing Kinase