Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, N-0424 Oslo, Norway;
K. G. Jebsen Centre for B Cell Malignancies, Institute for Clinical Medicine, University of Oslo, N-0318 Oslo, Norway; and
J Immunol. 2019 Aug 15;203(4):1055-1063. doi: 10.4049/jimmunol.1801660. Epub 2019 Jul 10.
Full T cell activation depends on stimulation of the TCR in conjunction with a costimulatory receptor. The involvement of costimulatory molecules is potent, and a mechanistic understanding of how downstream signaling is regulated is required to fully understand T cell responsiveness. In this study, a proteomic approach was taken to identify the interactomes of the coreceptors CD2 and CD28. These coreceptors are both positive regulators of T cell activation, but CD28 less potently induces TCR-proximal signaling. C-terminal Src kinase (CSK), a negative regulator of TCR signaling, was identified as a specific and direct interactor only of activated CD28. CSK is recruited to CD28 upon T cell activation, and the in vitro kinase activity of CSK is enhanced in the presence of phosphorylated CD28. Interruption of the CSK/CD28 interaction prior to TCR/CD28 costimulation induces a signaling response which mimics the more potent CD2-induced TCR-proximal pathway activation. Thus, CD28 functions as a novel adaptor protein for CSK, and CSK regulates signaling downstream of CD28.
T 细胞的完全激活依赖于 T 细胞受体（TCR）与共刺激受体的协同刺激。共刺激分子的参与作用非常强大，为了全面理解 T 细胞的反应性，需要对下游信号转导的调控机制有深入的了解。在这项研究中，我们采用蛋白质组学方法来鉴定核心受体 CD2 和 CD28 的相互作用组。这两个核心受体都是 T 细胞激活的正向调节剂，但 CD28 的 TCR 近端信号诱导能力较弱。C 端Src 激酶（CSK）是 TCR 信号的负调控因子，它被鉴定为仅与激活的 CD28 具有特异性和直接相互作用。CSK 在 T 细胞激活时被募集到 CD28 上，并且在存在磷酸化 CD28 的情况下，CSK 的体外激酶活性增强。在 TCR/CD28 共刺激之前中断 CSK/CD28 相互作用会诱导类似于更有效的 CD2 诱导的 TCR 近端途径激活的信号反应。因此，CD28 作为 CSK 的新型衔接蛋白发挥作用，CSK 调节 CD28 下游的信号转导。
