Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China.
La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
Nat Immunol. 2018 Jul;19(7):766-775. doi: 10.1038/s41590-018-0137-8. Epub 2018 Jun 20.
The mechanisms by which the sensitivity of naive CD4 T cells to stimulation by the cognate antigen via the T cell antigen receptor (TCR) determines their differentiation into distinct helper T cell subsets remain elusive. Here we demonstrate functional collaboration of the ubiquitin E3 ligases Itch and WWP2 in regulating the strength of the TCR signal. Mice lacking both Itch and WWP2 in T cells showed spontaneous autoimmunity and lung inflammation. CD4 T cells deficient in Itch and WWP2 exhibited hypo-responsiveness to TCR stimulation and a bias toward differentiation into the T2 subset of helper T cells. Itch and WWP2 formed a complex and cooperated to enhance TCR-proximal signaling by catalyzing the conjugation of atypical ubiquitin chains to the phosphatase SHP-1 and reducing the association of SHP-1 with the tyrosine kinase Lck. These findings indicate that targeted ubiquitination regulates the strength of the TCR signal and differentiation toward the T2 lineage.
幼稚 CD4 T 细胞通过 T 细胞抗原受体 (TCR) 对同源抗原刺激的敏感性决定其分化为不同的辅助性 T 细胞亚群的机制仍不清楚。在这里，我们证明了泛素 E3 连接酶 Itch 和 WWP2 在调节 TCR 信号强度方面的功能协作。T 细胞中缺乏 Itch 和 WWP2 的小鼠表现出自发性自身免疫和肺部炎症。缺乏 Itch 和 WWP2 的 CD4 T 细胞对 TCR 刺激的反应性降低，并偏向于分化为辅助性 T 细胞的 T2 亚群。Itch 和 WWP2 形成复合物并协同作用，通过催化将非典型泛素链连接到磷酸酶 SHP-1 上来增强 TCR 近端信号，并减少 SHP-1 与酪氨酸激酶 Lck 的结合。这些发现表明，靶向泛素化调节 TCR 信号的强度和向 T2 谱系的分化。
