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

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.

Control of neutrophil influx during peritonitis by transcriptional cross‐regulation of chemokine CXCL1 by IL‐17 and IFN‐γ

“…In humans, the gain‐of‐function STAT1 mutations inhibited the development of IL‐17‐producing T cells and impaired IL‐17 immunity [45]. Introduction of the human STAT1 mutation into mice decreased the number of IL‐17‐producing cells upon Candida albicans infection [46]. Moreover, the death receptor Fas was demonstrated to promote T H 17 cell development by preventing STAT1 activation [47].…”

STAT1 gain-of-function heterozygous cell models reveal diverse interferon-signature gene transcriptional responses

“…In the decade since STAT1 GOF was first described, strides have been made in characterizing the disorder and its underlying pathophysiology. A prominent example is the impaired Th17 response observed in most patients, which has been linked to predisposition to fungal and bacterial infections 14 , 20 , 21 . From an autoimmune standpoint, impaired type I IFN response has been proposed as a possible contributory mechanism, given the heightened IFN signature associated with other autoimmune and inflammatory conditions 22 – 24 .…”

Biological and clinical significance of T helper 17 cell deficiency: insight into monogenic defects

“…Investigation on individuals that are prone to chronic mucocutaneous candidiasis (CMC) with defects in Th17 development and functionality due to single nucleotide polymorphism or as segment of syndrome have elucidated the involvement of Th17 cells in the protection of human host (5,6).The processes of Th17 cell differentiation and inborn errors of Th17 cell function in affected patients have drawn attention in recent time (7). For instance, it has been reported that mutation in some genes such as DOCK8, STAT3, STAT1, AIRE, IL-17RA, IL-17F led to impairment of Th17 development and function in humans (8).…”

“…This is responsible for the abnormal IL-17 + T-cell development, impacting on IL-17 + T cell-mediated responses that are often antifungal in effect. 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(40).…”