Gain-of-function human <i>STAT1</i> mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

TLDR

Chronic mucocutaneous candidiasis (CMCD) can arise from autosomal dominant IL‑17F deficiency or autosomal recessive IL‑17RA deficiency, and loss‑of‑function STAT1 mutations are known to predispose to mycobacterial and viral infections through impaired STAT1‑dependent cytokine responses. Whole‑exome sequencing of 47 patients from 20 kindreds identified heterozygous germline STAT1 mutations associated with autosomal dominant CMCD. These 12 heterozygous STAT1 alleles are gain‑of‑function, residing in the coiled‑coil domain and impairing STAT1 dephosphorylation, which amplifies STAT1 and STAT3 cytokine signaling and blocks IL‑17A/F/22‑producing T‑cell development, thereby causing AD CMCD.

Abstract

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.