Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets.
Constitutive Lck Activity Drives Sensitivity Differences between CD8+ Memory T Cell Subsets.
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DOI：
10.4049/jimmunol.1600178
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发表时间：
2016-07-15
期刊：
影响因子：
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通讯作者：
Krogsgaard M
中科院分区：
文献类型：
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作者：
Moogk D;Zhong S;Yu Z;Liadi I;Rittase W;Fang V;Dougherty J;Perez-Garcia A;Osman I;Zhu C;Varadarajan N;Restifo NP;Frey AB;Krogsgaard M
CD8+T细胞在经历抗原后会产生更高的敏感性，并且T细胞记忆亚群之间的敏感性存在差异。记忆亚群之间的不同TCR信号如何导致敏感度差异尚不清楚。我们发现，在小鼠效应记忆T细胞中，超过50%的淋巴细胞特异性蛋白酪氨酸激酶(Lck)以结构性活性构象存在，而在中央记忆T细胞(Tcm)中，这一比例不到20%。在接近Lck信号转导通路时，我们观察到TCR结扎组与Tcm组相比，TcR结扎后TEM中ZAP-70的磷酸化增强。此外，我们观察到，与Tcm相比，TEM具有更好的细胞毒效应功能，并提供证据表明，这是由于TCR-近端信号的幅度降低，导致Tcm达到阈值信号的可能性较低。我们提供的证据表明，CD8+Tcm和TEMLCK构造活性的差异是由于SH2结构域包含的磷酸酶-1(SHP-1)和C-末端Src激酶(CSK)的不同调控，并通过早期TCR信号的模拟来揭示这些差异的意义。我们发现，抑制SHP-1会导致中药中结构性LCK活性增加到与透射电子显微镜相似的水平，并增加中药的细胞毒效应功能。总之，这项工作证明了结构性Lck活性在控制抗原敏感性中的作用，并提示TCR近端信号成分的不同活性可能有助于建立中医和透射电子显微镜的不同效应特性。这项工作也确定了SHP-1作为一个潜在的靶点来改善中药的细胞毒效应功能，用于过继细胞治疗应用。
CD8+ T cells develop increased sensitivity following antigen experience, and differences in sensitivity exist between T cell memory subsets. How differential TCR signaling between memory subsets contributes to sensitivity differences is unclear. We show in mouse effector memory T cells (TEM) that more than 50% of lymphocyte-specific protein tyrosine kinase (Lck) exists in a constitutively active conformation, compared with less than 20% in central memory T cells (TCM). Immediately proximal to Lck signaling, we observed enhanced Zap-70 phosphorylation in TEM following TCR ligation compared with TCM. Further, we observed superior cytotoxic effector function in TEM compared with TCM, and provide evidence that this results from a lower probability of TCM reaching threshold signaling due to the decreased magnitude of TCR-proximal signaling. We provide evidence that the differences in Lck constitutive activity between CD8+ TCM and TEM are due to differential regulation by SH2 domain-containing phosphatase-1 (Shp-1) and C-terminal Src kinase (Csk), and use modeling of early TCR signaling to reveal the significance of these differences. We show that inhibition of Shp-1 results in increased constitutive Lck activity in TCM to levels similar to TEM, as well as increased cytotoxic effector function in TCM. Together, this work demonstrates a role for constitutive Lck activity in controlling antigen sensitivity, and suggests that differential activities of TCR-proximal signaling components may contribute to establishing the divergent effector properties of TCM and TEM. This work also identifies Shp-1 as a potential target to improve the cytotoxic effector functions of TCM for adoptive cell therapy applications.