Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice

被引:20
作者
Tamaura, Moe [1 ,2 ]
Satoh-Takayama, Naoko [2 ]
Tsumura, Miyuki [1 ]
Sasaki, Takaharu [2 ]
Goda, Satoshi [1 ]
Kageyama, Tomoko [2 ]
Hayakawa, Seiichi [1 ]
Kimura, Shunsuke [1 ]
Asano, Takaki [1 ]
Nakayama, Manabu [4 ]
Koseki, Haruhiko [5 ]
Ohara, Osamu [6 ,7 ]
Okada, Satoshi [1 ]
Ohno, Hiroshi [2 ,3 ]
Kobayashi, Masao [1 ]
机构
[1] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Pediat, Hiroshima 7348551, Japan
[2] RIKEN, Ctr Integrat Med Sci, Lab Intestinal Ecosyst, Yokohama, Kanagawa 2300045, Japan
[3] Yokohama City Univ, Grad Sch Med Life Sci, Dept Med Life Sci, Div Immunobiol, Yokohama, Kanagawa 2300045, Japan
[4] Kazusa DNA Res Inst, Dept Frontier Res & Dev, Kisarazu 2920818, Japan
[5] RIKEN, Lab Dev Genet, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan
[6] Kazusa DNA Res Inst, Dept Appl Genom, Kisarazu 2920818, Japan
[7] RIKEN, Lab Integrat Genom, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan
基金
日本学术振兴会;
关键词
chronic mucocutaneous candidiasis; interleukin-17; Th17; cells; CHRONIC MUCOCUTANEOUS CANDIDIASIS; FUNCTION SIGNAL TRANSDUCER; T-BET; HOST-DEFENSE; COMBINED IMMUNODEFICIENCY; INBORN-ERRORS; IMPAIR IL-17; TH17; CELLS; ACTIVATOR; EXPRESSION;
D O I
10.1093/intimm/dxz079
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Gain-of-function (GOF) mutations in the gene for signal transducer and activator of transcription 1 (STAT1) account for approximately one-half of patients with chronic mucocutaneous candidiasis (CMC) disease. Patients with GOF-STAT1 mutations display a broad variety of infectious and autoimmune manifestations in addition to CMC, and those with severe infections and/or autoimmunity have a poor prognosis. The establishment of safe and effective treatments based on a precise understanding of the molecular mechanisms of this disorder is required to improve patient care. To tackle this problem, we introduced the human R274Q GOF mutation into mice [GOF-Stat1 knock-in (GOF-Stat1(R274Q))]. To investigate the immune responses, we focused on the small intestine (SI), which contains abundant Th17 cells. Stat1(R274Q/R274Q) mice showed excess phosphorylation of STAT1 in CD4(+) T cells upon IFN-gamma stimulation, consistent with the human phenotype in patients with the R274Q mutation. We identified two subpopulations of CD4(+) T cells, those with 'normal' or 'high' level of basal STAT1 protein in Stat1(R274Q/R274Q) mice. Upon IFN-gamma stimulation, the 'normal' level CD4(+) T cells were more efficiently phosphorylated than those from WT mice, whereas the 'high' level CD4(+) T cells were not, suggesting that the level of STAT1 protein does not directly correlate with the level of pSTAT1 in the SI. Inoculation of Stat1(R274Q/R274Q) mice with Candida albicans elicited decreased IL-17-producing CD4(+)ROR gamma t(+) cells. Stat1(R274Q/R274Q) mice also excreted larger amounts of C. albicans DNA in their feces than control mice. Under these conditions, there was up-regulation of T-bet in CD4(+) T cells. GOF-Stat1(R274Q) mice thus should be a valuable model for functional analysis of this disorder.
引用
收藏
页码:259 / 272
页数:14
相关论文
共 87 条
  • [1] T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells
    Afkarian, M
    Sedy, JR
    Yang, J
    Jacobson, NG
    Cereb, N
    Yang, SY
    Murphy, TL
    Murphy, KM
    [J]. NATURE IMMUNOLOGY, 2002, 3 (06) : 549 - 557
  • [2] ATP drives lamina propria TH17 cell differentiation
    Atarashi, Koji
    Nishimura, Junichi
    Shima, Tatsuichiro
    Umesaki, Yoshinori
    Yamamoto, Masahiro
    Onoue, Masaharu
    Yagita, Hideo
    Ishii, Naoto
    Evans, Richard
    Honda, Kenya
    Takeda, Kiyoshi
    [J]. NATURE, 2008, 455 (7214) : 808 - U10
  • [3] Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells
    Atarashi, Koji
    Tanoue, Takeshi
    Ando, Minoru
    Kamada, Nobuhiko
    Nagano, Yuji
    Narushima, Seiko
    Suda, Wataru
    Imaoka, Akemi
    Setoyama, Hiromi
    Nagamori, Takashi
    Ishikawa, Eiji
    Shima, Tatsuichiro
    Hara, Taeko
    Kado, Shoichi
    Jinnohara, Toshi
    Ohno, Hiroshi
    Kondo, Takashi
    Toyooka, Kiminori
    Watanabe, Eiichiro
    Yokoyama, Shin-ichiro
    Tokoro, Shunji
    Mori, Hiroshi
    Noguchi, Yurika
    Morita, Hidetoshi
    Ivanov, Ivaylo I.
    Sugiyama, Tsuyoshi
    Nunez, Gabriel
    Camp, J. Gray
    Hattori, Masahira
    Umesaki, Yoshinori
    Honda, Kenya
    [J]. CELL, 2015, 163 (02) : 367 - 380
  • [4] Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1
    Baris, Safa
    Alroqi, Fayhan
    Kiykim, Ayca
    Karakoc-Aydiner, Elif
    Ogulur, Ismail
    Ozen, Ahmet
    Charbonnier, Louis-Marie
    Bakir, Mustafa
    Boztug, Kaan
    Chatila, Talal A.
    Barlan, Isil B.
    [J]. JOURNAL OF CLINICAL IMMUNOLOGY, 2016, 36 (07) : 641 - 648
  • [5] Increased STAT1 Amounts Correlate with the Phospho-STAT1 Level in STAT1 Gain-of-function Defects
    Bernasconi, Andrea R.
    Yancoski, Judith
    Villa, Mariana
    Oleastro, Matias M.
    Galicchio, Miguel
    Rossi, Jorge G.
    [J]. JOURNAL OF CLINICAL IMMUNOLOGY, 2018, 38 (07) : 745 - 747
  • [6] An ACT1 Mutation Selectively Abolishes Interleukin-17 Responses in Humans with Chronic Mucocutaneous Candidiasis
    Boisson, Bertrand
    Wang, Chenhui
    Pedergnana, Vincent
    Wu, Ling
    Cypowyj, Sophie
    Rybojad, Michel
    Belkadi, Aziz
    Picard, Capucine
    Abel, Laurent
    Fieschi, Claire
    Puel, Anne
    Li, Xiaoxia
    Casanova, Jean-Laurent
    [J]. IMMUNITY, 2013, 39 (04) : 676 - 686
  • [7] CANALES L, 1969, LANCET, V2, P567
  • [8] A 1-Year-Old Girl with a Gain-of-Function STAT1 Mutation Treated with Hematopoietic Stem Cell Transplantation
    Carlos Aldave, Juan
    Cachay, Enrique
    Nunez, Luis
    Chunga, Ausberto
    Murillo, Sergio
    Cypowyj, Sophie
    Bustamante, Jacinta
    Puel, Anne
    Casanova, Jean-Laurent
    Koo, Armando
    [J]. JOURNAL OF CLINICAL IMMUNOLOGY, 2013, 33 (08) : 1273 - 1275
  • [9] Anticandidal immunity and vaginitis: Novel opportunities for immune intervention
    Cassone, Antonio
    De Bernardis, Flavia
    Santoni, Giorgio
    [J]. INFECTION AND IMMUNITY, 2007, 75 (10) : 4675 - 4686
  • [10] CHILGREN RA, 1967, LANCET, V2, P688