DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency.

Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 () cause immune dysregulation with autoimmunity, immunodeficiency and lymphoproliferation (IDAIL). Incomplete penetrance and variable expressivity are characteristic of IDAIL caused by CTLA-4 haploinsufficiency (CTLA-4h), pointing to a role for genetic modifiers. Here, we describe an IDAIL proband carrying a maternally inherited pathogenic variant and a paternally inherited rare LoF missense variant in which encodes for the β-glucan pattern recognition receptor DECTIN-1. The variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (T) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor-β. Consistent with DECTIN-1's T-boosting ability, partial DECTIN-1 deficiency exacerbated the T defect conferred by CTL4-4h. DECTIN-1/ emerges as a modifier gene in CTLA-4h, increasing expressivity of variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.