Innate immune side of STAT1 GOF

Abstract

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, which remain mechanistically unexplained. Surprisingly, little is known about the biological consequences of augmented STAT1 signaling in innate immune cells. Considering the importance of innate immune mechanisms in antifungal defense and autoimmune complications, we examined the phenotype and function of monocytes and dendritic cells in a cohort of patients with STAT1 GOF.We demonstrated that human ex vivo STAT1 GOF monocytes are characterized by proinflammatory phenotype and strong inflammatory skew of their secretory cytokine profile. The distribution of monocytes subpopulations’ is altered and they exhibit various functional abnormalities, which might represent a contributing mechanism in the pathogenesis of STAT1 GOF-associated autoimmunity, e.g., a selectively enhanced responsiveness to TLR7/8 stimulation, but not to other TLR ligands. Importantly, some of these features extend to STAT1 GOF myeloid dendritic cells, suggesting that the alterations observed in monocytes are, in fact, intrinsic due to STAT1 mutation, and not mere secondary consequence of the chronic inflammatory milieu.To follow up on the ex vivo data, we employed an in vitro model of monocyte-derived DC (moDC) and tolerogenic DC (tDC). 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.In conclusion, we present first-ever data implying a direct involvement of monocytes and DCs in the STAT1 GOF-associated immune pathology, possibly contributing to both autoimmune manifestations and the failure of antifungal defense. Our work thus highlights a yet understudied innate immune background in STAT1 GOF which should be dissected in details by future research.