Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a 
primary immunodeficiency caused by mutations in the autoimmune regulator gene 
(AIRE). Patients with AIRE mutations are susceptible to Candida albicans 
infection and present with autoimmune disorders. We previously demonstrated that 
cytoplasmic AIRE regulates the Syk-dependent Dectin-1 pathway. In this study, we 
further evaluated direct contact with fungal elements, synapse formation, and 
the response of macrophage-like THP-1 cells to C. albicans hyphae to determine 
the role of AIRE upon Dectin receptors function and signaling. We examined the 
fungal synapse (FS) formation in wild-type and AIRE-knockdown THP-1 cells 
differentiated to macrophages, as well as monocyte-derived macrophages from 
APECED patients. We evaluated Dectin-2 receptor signaling, phagocytosis, and 
cytokine secretion upon hyphal stimulation. AIRE co-localized with Dectin-2 and 
Syk at the FS upon hyphal stimulation of macrophage-like THP-1 cells. 
AIRE-knockdown macrophage-like THP-1 cells exhibited less Dectin-1 and Dectin-2 
receptors accumulation, decreased signaling pathway activity at the FS, lower C. 
albicans phagocytosis, and less lysosome formation. Furthermore, IL-1β, IL-6, or 
TNF-α secretion by AIRE-knockdown macrophage-like THP-1 cells and AIRE-deficient 
patient macrophages was decreased compared to control cells. Our results suggest 
that AIRE modulates the FS formation and hyphal recognition and help to 
orchestrate an effective immune response against C. albicans.