ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells.
ADAM17-dependent proteolysis of L-selectin promotes early clonal expansion of cytotoxic T cells.
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L-选择素的 ADAM17 依赖性蛋白水解促进细胞毒性 T 细胞的早期克隆扩增。
DOI：
10.1038/s41598-019-41811-z
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发表时间：
2019
影响因子：
4.6
通讯作者：
Mohammed RN
中科院分区：
文献类型：
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作者：
Mohammed RN
T细胞上的L-选择素是一种最为人所知的粘附分子，它支持将血源性幼稚细胞和中央记忆细胞募集到淋巴结中。胞外域的蛋白水解脱落被认为将活化的T细胞从淋巴结重定向到感染部位。然而，我们已经表明，活化的T细胞在淋巴结出口之前重新表达L-选择素，并使用L-选择素定位到病毒感染的组织。因此，我们考虑了T细胞活化过程中L-选择素蛋白水解的其他作用。在这项研究中，我们使用的T细胞表达可切割或不可切割的L-选择素，并确定在病毒感染的小鼠的T细胞活化的L-选择素蛋白水解的影响。我们确认了ADAM 17在小鼠和人T细胞中TCR诱导的L-选择素蛋白水解中的重要和非冗余作用，并表明L-选择素切割不调节通过CD 69或TCR内化测量的T细胞活化。病毒感染小鼠后，L-选择素蛋白水解促进细胞毒性T细胞的早期克隆扩增，导致比不能切割L-选择素的T细胞增加8倍。不能切割L-选择素的T细胞在体外表现出延迟的增殖，这与较低的CD 25表达相关。基于这些结果，我们提出，ADAM 17依赖的蛋白水解的L-选择素应被视为调节T细胞活化的免疫活性的网站。
L-selectin on T-cells is best known as an adhesion molecule that supports recruitment of blood-borne naïve and central memory cells into lymph nodes. Proteolytic shedding of the ectodomain is thought to redirect activated T-cells from lymph nodes to sites of infection. However, we have shown that activated T-cells re-express L-selectin before lymph node egress and use L-selectin to locate to virus-infected tissues. Therefore, we considered other roles for L-selectin proteolysis during T cell activation. In this study, we used T cells expressing cleavable or non-cleavable L-selectin and determined the impact of L-selectin proteolysis on T cell activation in virus-infected mice. We confirm an essential and non-redundant role for ADAM17 in TCR-induced proteolysis of L-selectin in mouse and human T cells and show that L-selectin cleavage does not regulate T cell activation measured by CD69 or TCR internalisation. Following virus infection of mice, L-selectin proteolysis promoted early clonal expansion of cytotoxic T cells resulting in an 8-fold increase over T cells unable to cleave L-selectin. T cells unable to cleave L-selectin showed delayed proliferationin vitrowhich correlated with lower CD25 expression. Based on these results, we propose that ADAM17-dependent proteolysis of L-selectin should be considered a regulator of T-cell activation at sites of immune activity.