2026-04-29T12:24:16Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/168592024-09-27T08:42:52Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Turnbull, Cynthia author Bones, Josiah author Stanley, Maurice author Medhavy, Arti author Wang, Hao author Lorenzo, Ayla May D author Cappello, Jean author Shanmuganandam, Somasundhari author Pandey, Abhimanu author Seneviratne, Sandali author Brown, Grant J author Meng, Xiangpeng author Fulcher, David author Burgio, Gaetan author Man, Si Ming author de Lucas Collantes, Carmen author Gasior, Mercedes author López Granados, Eduardo author Martin, Pilar author Jiang, Simon H author Cook, Matthew C author Ellyard, Julia I author Athanasopoulos, Vicki author Corry, Ben author Canete, Pablo F author Vinuesa, Carola G author 2023-12-08 Autosomal 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. Sci Adv. 2023 Dec 8;9(49):eadi9566. 10.1126/sciadv.adi9566 2375-2548 Science advances 38055819 http://hdl.handle.net/20.500.12105/16859 DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency.