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

Abstract

Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (<i>CTLA4</i>) 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 <i>CTLA4</i> variant and a paternally inherited rare LoF missense variant in <i>CLEC7A,</i> which encodes for the β-glucan pattern recognition receptor DECTIN-1. The <i>CLEC7A</i> variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (T_reg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor-β. Consistent with DECTIN-1's T_reg-boosting ability, partial DECTIN-1 deficiency exacerbated the T_reg defect conferred by CTL4-4h. DECTIN-1/<i>CLEC7A</i> emerges as a modifier gene in CTLA-4h, increasing expressivity of <i>CTLA4</i> variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.