Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States.
Department of Pediatrics, Division of Allergy, Asthma, and Immunology, Children's Mercy Hospital, Kansas City, MO, United States.
Cell Immunol. 2020 Jul;353:104130. doi: 10.1016/j.cellimm.2020.104130. Epub 2020 May 13.
Previously our lab has shown that co-stimulation of human T cells through different co-stimulatory molecules tune differentiation to different phenotypes. An open question is where in the signaling pathways induced by the co-stimulation do differences occur that contribute to outcome of differentiation. In this project, we investigate the early signaling process by comparing events that follow engagement of CD45 alone or in association with a co-stimulatory molecule: CD28. CD45 plays a crucial role to initiate T cell signaling by dephosphorylating a negatively regulatory tyrosine residue in Src family kinases such as Lck. First, we observed that engagement of CD45 alone induced signaling in T cells. We observed that TCR/CD3 stimulation with CD45 promoted prolonged Lck association with TCR/CD3 complex and Lck remained associated during TCR/CD3 + CD28 + CD45 stimulation as well. We concluded that Lck association is dependent on TCR/CD3 and CD45 engagement. Hence, CD45 altered early signaling events in T cells.
此前，我们实验室已经表明，通过不同的共刺激分子对人 T 细胞进行共刺激，可以调节其分化为不同的表型。一个悬而未决的问题是，在共刺激诱导的信号通路中，哪些差异会导致分化结果的不同。在这个项目中，我们通过比较单独或与共刺激分子（CD28）结合后 CD45 参与所引发的早期信号事件来研究早期信号过程。CD45 通过去磷酸化 Src 家族激酶（如 Lck）中的一个负调控酪氨酸残基，在启动 T 细胞信号转导中发挥着至关重要的作用。首先，我们观察到 CD45 单独结合即可诱导 T 细胞信号转导。我们观察到，与 CD45 结合的 TCR/CD3 刺激促进了 Lck 与 TCR/CD3 复合物的长时间结合，并且在 TCR/CD3+CD28+CD45 刺激期间 Lck 也保持与 TCR/CD3 复合物的结合。我们得出结论，Lck 的结合依赖于 TCR/CD3 和 CD45 的结合。因此，CD45 改变了 T 细胞的早期信号事件。
