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

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.