Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/16859
Título
DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency.
Autor(es)
Turnbull, Cynthia | Bones, Josiah | Stanley, Maurice | Medhavy, Arti | Wang, Hao | Lorenzo, Ayla May D | Cappello, Jean | Shanmuganandam, Somasundhari | Pandey, Abhimanu | Seneviratne, Sandali | Brown, Grant J | Meng, Xiangpeng | Fulcher, David | Burgio, Gaetan | Man, Si Ming | de Lucas Collantes, Carmen | Gasior, Mercedes | López Granados, Eduardo | Martin, Pilar CNIC | Jiang, Simon H | Cook, Matthew C | Ellyard, Julia I | Athanasopoulos, Vicki | Corry, Ben | Canete, Pablo F | Vinuesa, Carola G
Fecha de publicación
2023-12-08
Cita
Sci Adv. 2023 Dec 8;9(49):eadi9566.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
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