Aberrant autophagy and skewed inflammatory and tolerogenic functions in
STAT1 gain-of-function dendritic cells
Abstract
Signal transducer and activator of transcription 1 (STAT1)
gain-of-function (GOF) mutations underlie an inborn error of immunity
called chronic mucocutaneous candidiasis. Beyond the fungal
susceptibility, attributed to Th17 failure, over half of the reported
patients suffer from autoimmune manifestations, the mechanism of which
has not been explained yet. Dendritic cells (DCs) have been implicated
in the pathogenesis of various autoimmune disorders, however, to date
they have not been studied in STAT1 GOF CMC. We hypothesized that the
STAT1 mutations would affect DCs’ properties and alter their
inflammatory and tolerogenic functions. To test the hypothesis, we
generated monocyte-derived DCs (moDCs) and tolerogenic DCs (tDCs) from
freshly isolated STAT1 GOF patients’ monocytes cultivated in the
presence of IL-4 and GM-CSF (moDCs), and tolerogenic factors vitamin D2
and dexamethasone (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
defective autophagy, proinflammatory skew and loss of tolerogenic
functions. The results suggested that DCs play an important role in the
immune dysregulation in STAT1 GOF CMC and may contribute to the
disease-associated autoimmune manifestations via alteration in various
cellular mechanism, including autophagic processes.