論文 - 詳細
| RRC ID | 66406 |
|---|---|
| 著者 | Tamaura M, Satoh-Takayama N, Tsumura M, Sasaki T, Goda S, Kageyama T, Hayakawa S, Kimura S, Asano T, Nakayama M, Koseki H, Ohara O, Okada S, Ohno H, Kobayashi M. |
| タイトル | Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice. |
| ジャーナル | Int Immunol |
| Abstract |
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-Stat1R274Q)]. To investigate the immune responses, we focused on the small intestine (SI), which contains abundant Th17 cells. Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1 in CD4+ T cells upon IFN-γ 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 Stat1R274Q/R274Q mice. Upon IFN-γ 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 Stat1R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4+RORγt+ cells. Stat1R274Q/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-Stat1R274Q mice thus should be a valuable model for functional analysis of this disorder. |
| 巻・号 | 32(4) |
| ページ | 259-272 |
| 公開日 | 2020-4-12 |
| DOI | 10.1093/intimm/dxz079 |
| PII | 5684934 |
| PMID | 31867619 |
| MeSH | Animals Candida albicans / immunology Gain of Function Mutation / genetics* Humans Interleukin-17 / biosynthesis Interleukin-17 / immunology* Mice Mice, Inbred C57BL STAT1 Transcription Factor / genetics* STAT1 Transcription Factor / immunology Th17 Cells |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 一般微生物 | JCM1542 |