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. 2020 Apr 12;32(4):259-272.
doi: 10.1093/intimm/dxz079.

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

Moe Tamaura  1   2 , Naoko Satoh-Takayama  2 , Miyuki Tsumura  1 , Takaharu Sasaki  2 , Satoshi Goda  1 , Tomoko Kageyama  2 , Seiichi Hayakawa  1 , Shunsuke Kimura  1 , Takaki Asano  1 , Manabu Nakayama  3 , Haruhiko Koseki  4 , Osamu Ohara  5   6 , Satoshi Okada  1 , Hiroshi Ohno  2   7 , Masao Kobayashi  1
Affiliations

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

Moe Tamaura et al. 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.

Keywords: Th17 cells; chronic mucocutaneous candidiasis; interleukin-17.

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