Turnbull, CynthiaBones, JosiahStanley, MauriceMedhavy, ArtiWang, HaoLorenzo, Ayla May DCappello, JeanShanmuganandam, SomasundhariPandey, AbhimanuSeneviratne, SandaliBrown, Grant JMeng, XiangpengFulcher, DavidBurgio, GaetanMan, Si Mingde Lucas Collantes, CarmenGasior, MercedesLópez Granados, EduardoMartin, PilarJiang, Simon HCook, Matthew CEllyard, Julia IAthanasopoulos, VickiCorry, BenCanete, Pablo FVinuesa, Carola G2023-12-202023-12-202023-12-08Sci Adv. 2023 Dec 8;9(49):eadi9566.http://hdl.handle.net/20.500.12105/16859Autosomal dominant loss-of-function (LoF) variants in cytotoxic T-lymphocyte associated protein 4 (CTLA4) 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 CTLA4 variant and a paternally inherited rare LoF missense variant in CLEC7A, which encodes for the β-glucan pattern recognition receptor DECTIN-1. The CLEC7A variant led to a loss of DECTIN-1 dimerization and surface expression. Notably, DECTIN-1 stimulation promoted human and mouse regulatory T cell (Treg) differentiation from naïve αβ and γδ T cells, even in the absence of transforming growth factor-β. Consistent with DECTIN-1's Treg-boosting ability, partial DECTIN-1 deficiency exacerbated the Treg defect conferred by CTL4-4h. DECTIN-1/CLEC7A emerges as a modifier gene in CTLA-4h, increasing expressivity of CTLA4 variants and acting in functional epistasis with CTLA-4 to maintain immune homeostasis and tolerance.engVoRhttp://creativecommons.org/licenses/by/4.0/HaploinsufficiencyLectins, C-TypeAnimalsHumansMiceAutoimmunityCTLA-4 AntigenAtribución 4.0 Internacional38055819949eadi956610.1126/sciadv.adi95662375-2548Science advancesopen access