Cytotoxic T lymphocytes (CTLs) are key effector cells in the immune response against viruses and cancers, killing targets with high precision. Target cell recognition by CTL triggers rapid polarization of intracellular organelles toward the synapse formed with the target cell, delivering cytolytic granules to the immune synapse. Single amino acid changes within peptides binding MHC class I (pMHCs) are sufficient to modulate the degree of killing, but exactly how this impacts the choreography of centrosome polarization and granule delivery to the target cell remains poorly characterized. Here we use 4D imaging and find that the pathways orchestrating killing within CTL are conserved irrespective of the signal strength. However, the rate of initiation along these pathways varies with signal strength. We find that increased strength of signal leads to an increased proportion of CTLs with prolonged dwell times, initial Ca2+ fluxes, centrosome docking, and granule polarization. Hence, TCR signal strength modulates the rate but not organization of effector CTL responses.

中文翻译：

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信号强度控制杀伤过程中 CTL 内的极化率

细胞毒性 T 淋巴细胞 (CTL) 是针对病毒和癌症的免疫反应中的关键效应细胞，能够高精度地杀死目标。CTL 识别靶细胞会触发细胞内细胞器向与靶细胞形成的突触快速极化，将溶细胞颗粒递送至免疫突触。结合 I 类 MHC (pMHC) 的肽内的单个氨基酸变化足以调节杀伤程度，但这种变化究竟如何影响中心体极化和颗粒递送至靶细胞的编排仍不清楚。在这里，我们使用 4D 成像，发现无论信号强度如何，CTL 内协调杀伤的通路都是保守的。然而，沿着这些路径的启动速率随信号强度而变化。我们发现，信号强度的增加会导致 CTL 比例增加，并延长停留时间、初始 Ca2+ 通量、中心体对接和颗粒极化。因此，TCR 信号强度调节效应 CTL 响应的速率，但不调节其组织。