The kinase LCK and CD4/CD8 co-receptors are crucial components of the T cell antigen receptor (TCR) signaling machinery, leading to key T cell fate decisions. Despite decades of research, the roles of CD4–LCK and CD8–LCK interactions in TCR triggering in vivo remain unknown. In this study, we created animal models expressing endogenous levels of modified LCK to resolve whether and how co-receptor-bound LCK drives TCR signaling. We demonstrated that the role of LCK depends on the co-receptor to which it is bound. The CD8-bound LCK is largely dispensable for antiviral and antitumor activity of cytotoxic T cells in mice; however, it facilitates CD8⁺ T cell responses to suboptimal antigens in a kinase-dependent manner. By contrast, the CD4-bound LCK is required for efficient development and function of helper T cells via a kinase-independent stabilization of surface CD4. Overall, our findings reveal the role of co-receptor-bound LCK in T cell biology, show that CD4- and CD8-bound LCK drive T cell development and effector immune responses using qualitatively different mechanisms and identify the co-receptor–LCK interactions as promising targets for immunomodulation.

激酶 LCK 和 CD4/CD8 共受体是 T 细胞抗原受体 (TCR) 信号机制的重要组成部分，导致关键的 T 细胞命运决定。尽管进行了数十年的研究，CD4-LCK 和 CD8-LCK 相互作用在体内触发 TCR 中的作用仍然未知。在这项研究中，我们创建了表达内源性修饰 LCK 水平的动物模型，以解决共受体结合的 LCK 是否以及如何驱动 TCR 信号转导。我们证明了 LCK 的作用取决于它所结合的辅助受体。CD8 结合的 LCK 在很大程度上对于小鼠细胞毒性 T 细胞的抗病毒和抗肿瘤活性是可有可无的；然而，它促进 CD8 ⁺T 细胞以激酶依赖性方式对次优抗原作出反应。相比之下，CD4 结合的 LCK 是辅助性 T 细胞通过不依赖于激酶的表面 CD4 稳定作用有效发育和发挥功能所必需的。总体而言，我们的研究结果揭示了共同受体结合的 LCK 在 T 细胞生物学中的作用，表明 CD4 和 CD8 结合的 LCK 使用质量不同的机制驱动 T 细胞发育和效应免疫反应，并将共同受体-LCK 相互作用确定为有希望的免疫调节靶点。