CD8⁺ T-cell responses are meticulously orchestrated processes regulated by intercellular receptor:ligand interactions. These interactions critically control the dynamics of CD8⁺ T-cell populations that is crucial to overcome threats such as viral infections or cancer. Yet, the mechanisms governing these dynamics remain incompletely elucidated. Here, we identified a hitherto unknown T-cell referred function of the self-ligating surface receptor SLAMF7 (CD319) on CD8⁺ T cells during initiation of cytotoxic T-cell responses. According to its cytotoxicity related expression on T effector cells, we found that CD8⁺ T cells could utilize SLAMF7 to transduce environmental cues into cellular interactions and information exchange. Indeed, SLAMF7 facilitated a dose-dependent formation of stable homotypic contacts that ultimately resulted in stable cell-contacts, quorum populations and commitment to expansion and differentiation. Using pull-down assays and network analyses, we identified novel SLAMF7-binding intracellular signaling molecules including the CRK, CRKL, and Nck adaptors, which are involved in T-cell contact formation and may mediate SLAMF7 functions in sensing and adhesion. Hence, providing SLAMF7 signals during antigen recognition of CD8⁺ T cells enhanced their overall magnitude, particularly in responses towards low-affinity antigens, resulting in a significant boost in their proliferation and cytotoxic capacity. Overall, we have identified and characterized a potent initiator of the cytotoxic T lymphocyte response program and revealed advanced mechanisms to improve CD8⁺ T-cell response decisions against weak viral or tumor-associated antigens, thereby strengthening our defense against such adversaries.

CD8⁺ T 细胞反应是由细胞间受体：配体相互作用调节的精心编排的过程。这些相互作用关键地控制着 CD8⁺ T 细胞群的动力学，这对于克服病毒感染或癌症等威胁至关重要。然而，控制这些动态的机制仍未完全阐明。在这里，我们确定了在细胞毒性 T 细胞反应启动期间 CD8⁺ T 细胞上的自连接表面受体 SLAMF7 （CD319） 的迄今未知的 T 细胞牵涉功能。根据其在 T 效应细胞上的细胞毒性相关表达，我们发现 CD8⁺ T 细胞可以利用 SLAMF7 将环境线索转导到细胞相互作用和信息交换中。事实上，SLAMF7 促进了稳定同型接触的剂量依赖性形成，最终导致稳定的细胞接触、群体群以及对扩增和分化的承诺。使用沉降测定和网络分析，我们鉴定了新的 SLAMF7 结合细胞内信号分子，包括 CRK 、 CRKL 和 Nck 接头，它们参与 T 细胞接触的形成，并可能介导 SLAMF7 在感应和粘附中的功能。因此，在 CD8⁺ T 细胞的抗原识别过程中提供 SLAMF7 信号增强了它们的整体幅度，特别是在对低亲和力抗原的反应中，从而显着提高了它们的增殖和细胞毒性能力。 总体而言，我们已经确定并表征了细胞毒性 T 淋巴细胞反应程序的有效启动因子，并揭示了改善 CD8⁺ T 细胞对弱病毒或肿瘤相关抗原的反应决策的先进机制，从而加强我们对此类对手的防御。