Organization of proximal signal initiation at the TCR:CD3 complex.
Organization of proximal signal initiation at the TCR:CD3 complex.
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DOI：
10.1111/j.1600-065x.2009.00843.x
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发表时间：
2009-11
影响因子：
8.7
通讯作者：
Vignali DA
中科院分区：
文献类型：
--
作者：
Guy CS;Vignali DA
抗原识别后导致T细胞活化的一系列事件已被广泛研究。尽管配体结合和这种细胞外相互作用传递到一个有效的细胞内信号序列的确切机制仍然不完整，但多年来人们已经知道，T细胞受体(TCR)：CD3复合体的免疫受体酪氨酸激活基序(ITAM)是启动这一信号级联反应所必需的，因为多种蛋白酪氨酸激酶、信号中间产物和适配分子的招募和激活。然而，目前尚不清楚为什么TCR：CD3复合体需要10个ITAM，而许多其他含有ITAM的免疫受体，如Fc受体(FCR)和B细胞受体(BCR)，包含的ITAM要少得多。我们最近证明了T细胞发育和激活的各种参数受TCR：CD3复合体中ITAM的数量、位置和类型的影响，从而提出TCR具有“可伸缩的信号”能力，从而促进各种T细胞功能的启动和协调。虽然许多潜在的机制仍然是假设的，本综述旨在将我们从传统的生化分析中获得的关于T细胞信号的启动和多样化的知识，与来自分子和荧光显微镜分析的更新证据相结合，以提出TCR的更广泛的目的：CD3 ITAM。单个ITAM不仅负责信号的启动，还可能负责信号和调节分子的差异化招募，最终影响T细胞的发育、激活和分化。
The series of events leading to T cell activation following antigen recognition has been extensively investigated. Although the exact mechanisms of ligand binding and transmission of this extracellular interaction into a productive intracellular signaling sequence remains incomplete, it has been known for many years that the immunoreceptor tyrosine activation motifs (ITAMs) of the T cell receptor (TCR):CD3 complex are required for initiation of this signaling cascade due to the recruitment and activation of multiple protein tyrosine kinases, signaling intermediates and adapter molecules. It however remains unclear why the TCR:CD3 complex requires 10 ITAMs, whilst many other ITAM-containing immune receptors, such as Fc receptors (FcR) and the B cell receptor (BCR), contain far fewer ITAMs. We have recently demonstrated that various parameters of T cell development and activation are influenced by the number, as well as location and type, of ITAM within the TCR:CD3 complex and hence propose that the TCR is capable of ‘scalable signaling’ that facilitates the initiation and orchestration of diverse T cell functions. While many of the underlying mechanisms remain hypothetical, this review intends to amalgamate what we have learned from conventional biochemical analyses, regarding initiation and diversification of T cell signaling, with more recent evidence from molecular and fluorescent microscopic analyses to propose a broader purpose for the TCR:CD3 ITAMs. Rather than simply signal initiation, individual ITAMs may also be responsible for the differential recruitment of signaling and regulatory molecules which ultimately affects T cell development, activation and differentiation.