特应性皮炎
调解人
生物
细胞生物学
细胞因子
T细胞受体
免疫学
信号转导
T细胞
癌症研究
免疫系统
作者
Jia Tong Loh,Joey Kay Hui Teo,Srinivasaraghavan Kannan,Chandra Verma,Anand Kumar Andiappan,Hong Hwa Lim,Kong‐Peng Lam
出处
期刊:Science Signaling
[American Association for the Advancement of Science (AAAS)]
日期:2023-10-31
卷期号:16 (809)
被引量:1
标识
DOI:10.1126/scisignal.adg5171
摘要
The scaffolding protein CARD11 is a critical mediator of antigen receptor signaling in lymphocytes. Hypomorphic (partial loss-of-function) mutations in CARD11 are associated with the development of severe atopic dermatitis, in which T cell receptor signaling is reduced and helper T cell differentiation is skewed to an allergy-associated type 2 phenotype. Here, we found that the docking protein DOK3 plays a key role in the pathogenesis of atopic dermatitis by suppressing CARD11 activity. DOK3 interacted with CARD11 and decreased its phosphorylation in T cells by recruiting the catalytic subunit of protein phosphatase 4, thereby dampening downstream signaling. Knocking out Dok3 enhanced the production of the cytokine IFN-γ by T cells, which conferred protection against experimental atopic dermatitis–like skin inflammation in mice. The expression of DOK3 was increased in T cells isolated from patients with atopic dermatitis and inversely correlated with IFNG expression. A subset of hypomorphic CARD11 variants found in patients with atopic dermatitis bound more strongly than wild-type CARD11 to DOK3. Our findings suggest that the strength of the interaction of DOK3 with CARD11 may predispose individuals to developing atopic dermatitis.
科研通智能强力驱动
Strongly Powered by AbleSci AI