| First Author | Turnbull C | Year | 2023 |
| Journal | Sci Adv | Volume | 9 |
| Issue | 49 | Pages | eadi9566 |
| PubMed ID | 38055819 | Mgi Jnum | J:358258 |
| Mgi Id | MGI:7564910 | Doi | 10.1126/sciadv.adi9566 |
| Citation | Turnbull C, et al. (2023) DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency. Sci Adv 9(49):eadi9566 |
| abstractText | 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 beta-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 (T(reg)) differentiation from naive alphabeta and gammadelta T cells, even in the absence of transforming growth factor-beta. Consistent with DECTIN-1's T(reg)-boosting ability, partial DECTIN-1 deficiency exacerbated the T(reg) 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. |
