Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice. (23rd December 2019)

• Record Type: Journal Article
• Authors: Tamaura, Moe; Satoh-Takayama, Naoko; Tsumura, Miyuki; Sasaki, Takaharu; Goda, Satoshi; Kageyama, Tomoko; Hayakawa, Seiichi; Kimura, Shunsuke; Asano, Takaki; Nakayama, Manabu; Koseki, Haruhiko; Ohara, Osamu; Okada, Satoshi; Ohno, Hiroshi; Kobayashi, Masao
• Is Part Of: International immunology. Volume 32:Number 4(2020)
• Page Start: 259
• Page End: 272
• Publication Date: 2019-12-23
• Subjects: chronic mucocutaneous candidiasis -- interleukin-17 -- Th17 cells; Immunology -- Periodicals; 616.079
• DOI: 10.1093/intimm/dxz079
• Languages: English
• ISSNs: 0953-8178

Abstract

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- 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-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 Stat1 R274Q/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 Stat1 R274Q/R274Q mice with Candida albicans elicited decreased IL-17-producing CD4 + RORγt + 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. Abstract : GOF- Stat1 R274Q mice are a model for CMC disease