| RRC ID |
66406
|
| Author |
Tamaura M, Satoh-Takayama N, Tsumura M, Sasaki T, Goda S, Kageyama T, Hayakawa S, Kimura S, Asano T, Nakayama M, Koseki H, Ohara O, Okada S, Ohno H, Kobayashi M.
|
| Title |
Human gain-of-function STAT1 mutation disturbs IL-17 immunity in mice.
|
| Journal |
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.
|
| Volume |
32(4)
|
| Pages |
259-272
|
| Published |
2020-4-12
|
| DOI |
10.1093/intimm/dxz079
|
| PII |
5684934
|
| PMID |
31867619
|
| MeSH |
Animals
Candida albicans / immunology
Gain of Function Mutation / genetics*
Humans
Interleukin-17 / biosynthesis
Interleukin-17 / immunology*
Mice
Mice, Inbred C57BL
STAT1 Transcription Factor / genetics*
STAT1 Transcription Factor / immunology
Th17 Cells
|
| Resource |
| General Microbes |
JCM1542 |
