title: Wild-type AIRE cooperates with p63 in HLA class II expression of medullary thymic stromal cells.
abstract: During T cell development in the thymus, autoreactive T cells are deleted through a mechanism that is actively supported by medullary epithelial cells. These epithelial cells possess particular transcription factors including autoimmune regulator (AIRE), which is responsible for regulating expression of self-antigens, as well as p63, a p53-like molecule. Here we present evidence suggesting interaction of AIRE with p63 through a SAND domain and a transactivation domain, respectively. Interestingly an AIRE molecule with a mutated SAND domain of G228W, whose genetic alteration is inherited in an autosomal dominant manner, could not establish a complex with p63 as indicated by immunoprecipitation and molecular modeling analyses. Further in vitro study indicated that the G228W mutation led to downregulation of the transcription levels of CIITA and, accordingly, the cell surface expression of HLA class II molecules in thymic epithelial cells with p63. This indicates novel involvement of AIRE and p63 in the regulation of HLA class II, and suggests that defects in the AIRE-p63 interaction may lead to malfunction of HLA-based selection of self-reactive helper CD4(+) T cells in the thymus.
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Tonooka
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kubo
authors.forename: Shingo
authors.initials: S
authors.lastname: Ichimiya
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamura
authors.forename: Tanja
authors.initials: T
authors.lastname: Ilmarinen
authors.forename: Ismo
authors.initials: I
authors.lastname: Ulmanen
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kimura
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Takano
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002675:Child, Preschool; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D025941:Protein Interaction Mapping; D017154:Stromal Cells / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D000949:Histocompatibility Antigens Class II; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000096927:AIRE Protein; C115051:TP63 protein, human