Wild-type AIRE cooperates with p63 in HLA class II expression of medullary thymic stromal cells.
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.
Tonooka
Akiko
A
Department of Pathology, Sapporo Medical University School of Medicine, South-1, West-17, Chuo-ku, Sapporo, Japan.
Kubo
Terufumi
T
Ichimiya
Shingo
S
Tamura
Yutaka
Y
Ilmarinen
Tanja
T
Ulmanen
Ismo
I
Kimura
Sachiko
S
Yokoyama
Shigeaki
S
Takano
Yoshihide
Y
Kikuchi
Tomoki
T
Sato
Noriyuki
N
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
D000949:Histocompatibility Antigens Class II; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000096927:AIRE Protein; C115051:TP63 protein, human