Journal
CLINICAL IMMUNOLOGY
Volume 246, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.clim.2022.109174
Keywords
Autophagy; Candidiasis; CMC; Dendritic cells; Ruxolitinib; STAT1; Tolerogenic
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STAT1 GOF mutations are responsible for chronic mucocutaneous candidiasis (CMC) and autoimmune manifestations. Our study shows that these mutations affect the properties of dendritic cells (DCs) and alter their functions. The altered DCs lose their tolerogenic functions, become proinflammatory, and have decreased ability to induce Th17 cells. The results suggest that DCs play a direct role in the immune pathology associated with STAT1 GOF mutations.
STAT1 gain-of-function (GOF) mutations underlie an inborn error of immunity hallmarked by chronic mucocutaneous candidiasis (CMC). Beyond the fungal susceptibility, attributed to Th17 failure, over half of the reported patients suffer from autoimmune manifestations, mechanism of which has not been explained yet. We hypothesized that the STAT1 mutations would affect dendritic cells' (DCs) properties and alter their inflammatory and tolerogenic functions. To test the hypothesis, we generated monocyte-derived DCs (moDCs) and tolerogenic DCs (tDCs). Functional and signaling studies, co-culture experiments and RNA sequencing demonstrated that STAT1 GOF DCs were profoundly altered in their phenotype and functions, characterized by loss of tolerogenic functions, proinflammatory skew and decreased capacity to induce Th17. Cytokine signaling, autophagy and metabolic processes were identified as the most prominently altered cellular processes. The results suggest that DCs are directly involved in STAT1 GOF-associated immune pathology, possibly contributing to both autoimmune manifestations and the failure of antifungal defense.
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