微绒毛是t细胞抗原搜索和配体检测的有效载体

En Cai, Kyle Marchuk, Casey Beppler, M. Krummel
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摘要

在抗原检测过程中,t细胞检测抗原呈递细胞(APCs)的表面,APCs可能主要显示非刺激性肽负载的主要组织相容性复合体(pMHCs)和罕见的同源抗原,这一过程涉及近距离(纳米尺度)的膜附着。因此,t细胞必须解决速度和灵敏度之间的经典权衡。长期以来,人们一直认为t细胞上的微绒毛作为感觉器官来实现搜索,但它们的策略尚不清楚。我们使用点阵光片显微镜和量子点突触接触映射显微镜来显示t细胞表面的微绒毛在抗原识别之前和过程中如何搜索对立的细胞和表面。我们发现t细胞表面的微绒毛在一分钟内通过异常扩散动态地测量大多数对立表面。t细胞受体(TCR)识别导致受体占据突起的选择性稳定,这是独立于酪氨酸激酶信号和肌动蛋白细胞骨架的。我们发现活化t细胞上的TCRs在细胞膜上的分布不均匀:一些TCRs集中在微绒毛上,而另一些TCRs在平坦的膜区域形成高密度斑块。许多微绒毛被tcr占据,但也有一小部分微绒毛未被tcr占据。TCR高密度斑块相对于微绒毛移动。在t细胞-APC相互作用过程中,我们观察到t细胞微绒毛深入到树突状细胞(DC)表面由面纱结构形成的三维口袋中,DC膜也符合t细胞微绒毛的容纳,这增加了t细胞与APC之间的有效密切接触面积。这种扫描模式使得t细胞在给定的时间内能够有效地扫描更多的APC表面。这项工作定义了在t细胞中进行配体检测的有效细胞搜索过程。引文格式:En Cai, Kyle Marchuk, Casey Beppler, Matthew Krummel。微绒毛能够实现高效的t细胞抗原搜索和配体检测[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志2019;7(2增刊):摘要nr B148。
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Abstract B148: Microvilli enable efficient T-cell antigen search and ligand detection
During antigen detection, T-cells survey the surface of antigen-presenting cells (APCs), which may display mainly nonstimulatory peptide-loaded major histocompatibility complexes (pMHCs) and only rare cognate antigen in a process involving close (nanometer-scale) membrane apposition. Thus, T-cell must solve a classic trade-off between speed and sensitivity. It has long been supposed that microvilli on T-cells act as sensory organs to enable search, but their strategy has been unknown. We used lattice light-sheet microscopy and quantum dot-enabled synaptic contact mapping microscopy to show how microvilli on the surface of T-cells search opposing cells and surfaces before and during antigen recognition. We uncovered that microvilli on T-cell surfaces dynamically survey the majority of opposing surfaces within one minute through anomalous diffusion. T-cell receptor (TCR) recognition resulted in selective stabilization of receptor-occupied protrusions, which was independent of tyrosine kinase signaling and the actin cytoskeleton. We revealed that TCRs on activated T-cells were nonuniformly distributed on cell membrane: some TCRs were concentrated on microvilli, while other TCRs formed high-density patches on flatter membrane regions. Many microvilli were TCR-occupied, but a small population of microvilli were found not occupied by TCRs. TCR high-density patches moved relative to microvilli. During T-cell-APC interaction, we observed T-cell microvilli projected deep into 3D pockets formed by veil structures on the surface of dendritic cells (DC), and DC membrane also conformed to accommodate T-cell microvilli, which increased the effective close-contact area between T-cell and APC. Such scanning pattern enabled T-cells to efficiently scan more APC surface in given time. This work defines the efficienT-cellular search process against which ligand detection takes place in T-cells. Citation Format: En Cai, Kyle Marchuk, Casey Beppler, Matthew Krummel. Microvilli enable efficient T-cell antigen search and ligand detection [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B148.
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