Moe Tamaura, Japan

Presenter Of 1 Presentation

E-Poster Discussion Innate Immunity

A MOUSE MODEL OF HUMAN DISEASE CAUSED BY GAIN-OF-FUNCTION STAT1 MUTATION

Lecture Time
13:50 - 13:57
Presenter
Room
Station 3
Date
19.09.2019, Thursday
Session Time
13:15 - 14:20
Presentation Topic
Innate Immunity

Abstract

Background and Aims

Patients with gain-of-function (GOF) STAT1 mutations display a variety of infectious and non-infectious manifestations. Some of them present severe infections and/or autoimmunity, resulting in poor prognosis. Therefore, it is imperative to establish effective treatments based on a precise understanding of the molecular mechanisms of this disorder. To tackle this problem and establish a disease mouse model, we generated GOF-Stat1 knock-in (GOF-Stat1R274Q) mice. Since a decrease in Th17 cells has been already correlated with the development of chronic mucocutaneous candidiasis in patients, we focused on the small intestine, which contains abundant Th17 cells in mice.

Methods

We generated GOF-Stat1R274Q mice by introducing the human R274Q mutation. Small intestinal lymphocytes from these mice were analyzed at 3 weeks after Candida albicans infection by flow cytometry, qPCR and RNA-seq.

Results

Stat1R274Q/R274Q mice showed excess phosphorylation of STAT1, with broad upregulation of IFN-stimulated genes, in CD4+ T cells upon IFN-γ stimulation, consistent with the phenotype of patients. Stat1R274Q/R274Q mice infected with C. albicans elicited decreased IL-17-producing CD4+RORγt+ cells and excreted larger amounts of C. albicans DNA in their feces compared to controls. Under these conditions, there was upregulation of T-bet in CD4+ T cells in Stat1R274Q/R274Q mice, which may play an inhibitory role in the regulation of RORγt and Th17 differentiation.

Conclusions

The GOF-Stat1R274Q mice generated in the current study turned out to be a reasonable model of patients with GOF STAT1 mutations and is expected to be a useful tool not only to pursue the molecular mechanism, but also to develop therapeutic strategies, of this disorder.

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