Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Nat Immunol. 2023 Jan;24(1):174-185. doi: 10.1038/s41590-022-01366-0. Epub 2022 Dec 23.
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) 信号转导机制的关键组成部分，导致关键的 T 细胞命运决定。尽管经过几十年的研究，CD4-LCK 和 CD8-LCK 相互作用在体内 TCR 触发中的作用仍不清楚。在这项研究中，我们创建了表达内源性修饰 LCK 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 LCK 的作用取决于与其结合的共受体。CD8 结合的 LCK 对于小鼠细胞毒性 T 细胞的抗病毒和抗肿瘤活性在很大程度上是可有可无的；然而，它以激酶依赖的方式促进了 CD8 T 细胞对低效抗原的反应。相比之下，CD4 结合的 LCK 通过激酶独立的表面 CD4 稳定作用对于辅助性 T 细胞的有效发育和功能是必需的。总体而言，我们的研究结果揭示了共受体结合的 LCK 在 T 细胞生物学中的作用，表明 CD4 和 CD8 结合的 LCK 通过使用不同的机制驱动 T 细胞发育和效应免疫反应，并确定了共受体-LCK 相互作用作为免疫调节的有前途的靶点。
