The TCR triggering puzzle
The TCR triggering puzzle
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DOI：
10.1016/s1074-7613(01)00155-8
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发表时间：
2001-06-01
期刊：
影响因子：
32.4
通讯作者：
van der Merwe, PA
中科院分区：
文献类型：
--
作者：
van der Merwe, PA
T细胞抗原识别需要T的结合（Lanzavecchia等人，1999），非常低密度的pepcell抗原受体（TCR）与MHC之间的复合物。一个可能的解决方案是提供抗原（通常是肽）和MHC分子（pepby两项研究使用可溶性TCR和pep-MHC，其中MHC）。这导致一系列信号传导事件，共同表明，在pep-MHC结合后，TCR/peptively称为TCR触发，其介导MHC复合物寡聚化（赖希et al.，1997; Alam通过一组TCR相关的跨膜信号转导等，1999年）。提出的机制是，在分子上，CD 3复合物。尽管人们对TCR或TCR/pep-MHC复合物进行了深入的研究，但关于TCR或TCR/pepto直接结合另一种TCR或TCR/pepto的能力这两个与MHC复合物相关的基本问题仍然没有令人满意的答案。然而，TCR/TCR触发的结构多样性。首先，上述TCR pep-MHC复合物通过什么机制引起了人们对与pep-MHC结合导致触发的怀疑？第二，结合诱导的自缔合是否可以是基因结合性质决定了TCR/pep-MHC相互作用的特定TCR/外周特征。此外，MHC相互作用会导致触发？我讨论了这两个单独的TCR/pep-MHC复合物是相当严重的这些问题在这里特别参考两个糖基化和周围的CD 3和辅助受体的重要最近的论文（贝克和威利，2001年; Kal-糖蛋白（Rudd等人，1999），这在Ergis等人看来，2001年），前者在此出版，排除两个或两个以上的豁免问题的直接物理关联。TCR/pep-MHC复合物。这些怀疑得到了支持。许多关于TCR触发的想法受到了本期报道的一项研究的影响，该研究通过从其他受体系统收集的见解寻找证据，在两种可溶性TCR/特别是受体中结合诱导的自缔合，如TCR，通过刺激肽-MHC系统发出信号（Baker和Wiley，2001）。使用sevlating酪氨酸磷酸化。然而，TCR/外周敏感技术，包括赖希潮汐-MHC相互作用所使用的技术，具有独特的功能，应等。（1997）和Alam et al.（1999），他们令人信服地铭记在心，当考虑可能的答案排除自协会在这些系统中。对上述问题的答复。首先，pep-MHC与其他研究结合（例如，威尔考克斯等人，1999），TCR上的结合位点以准随机方式产生-没有发现复杂结合动力学的证据，并且在自缔合的情况下应该观察到精细结构的巨大多样性，这表明TCR和pep-MHC结合表面相互作用。其次，结合诱导的自缔合不是一般的结合，在对TCR/pep-MHC相互作用的少数特征进行晶体学分析之后，因此是pep-MHC复合物的结合诱导的自缔合，已经清楚的是，结合诱导的自缔合不太可能是TCR触发的机制。构象变化模型通常提出，尽管在一定程度上受到限制，但其是相当可变的，即在与pep-MHC结合时，TCR经历了一个（Garcia等，1999; Hennecke和Wiley，2001）。对于以某种方式传递到例如相关CD 3信号传导机制周围测量的接合角的构象变化。用这些模型研究TCR/pep-MHC复合物的长轴的困难在于，它们令人难以置信地要求存在构象…
T cell antigen recognition requires the binding of the T (Lanzavecchia et al., 1999), very low densities of pepcell antigen receptor (TCR) to a complex between an MHC. A possible solution to this difficulty was provided antigen (usually peptide) and an MHC molecule (pepby two studies using soluble TCR and pep-MHC, which MHC). This leads to a series of signaling events collec- suggested that, following pep-MHC binding, TCR/peptively referred to as TCR triggering, which is mediated MHC complexes oligomerize (Reich et al., 1997; Alam by a group of TCR-associated transmembrane signaling et al., 1999). The mechanism proposed was that, upon molecules, the CD3 complex. Although it has been inten- binding, the TCR or TCR/pep-MHC complex acquires sively studied, we still do not have satisfactory answers the ability to bind directly to another TCR or TCR/pepto two fundamental and related questions concerning MHC complex. However, the structural diversity of TCR/TCR triggering. First, by what mechanism does TCR pep-MHC complexes noted above raises doubts as to binding to pep-MHC result in triggering? Second, what whether binding-induced self-association can be a genbinding property governs whether a particular TCR/pep- eral feature of TCR/pep-MHC interactions. Furthermore, MHC interaction will lead to triggering? I discuss both individual TCR/pep-MHC complexes are quite heavily of these questions here with special reference to two glycosylated and surrounded by CD3 and coreceptor important recent papers (Baker and Wiley, 2001; Kal- glycoproteins (Rudd et al., 1999), which would seem to ergis et al., 2001), the former being published in this preclude direct physical association of two or more issue of Immunity. TCR/pep-MHC complexes. These doubts are supported Many ideas concerning TCR triggering have been influ- by a study reported in this issue that looked for evidence enced by insights gleaned from other receptor systems, of binding-induced self-association in two soluble TCR/particularly receptors that, like the TCR, signal by stimu- pep-MHC systems (Baker and Wiley, 2001). Using sevlating tyrosine phosphorylation. However, the TCR/pep- eral sensitive techniques, including those used by Reich tide-MHC interaction has unique features that should et al.(1997) and Alam et al.(1999), they convincingly be borne in mind when considering possible answers rule out self-association in these systems. Taken toto the questions posed above. First, the pep-MHC bind- gether with other studies (eg, Willcox et al., 1999) that ing site on a TCR is generated in a quasi-random man- find no evidence of the complex binding kinetics that ner, and there is enormous diversity in the fine structure should be observed with self-association, this suggests of interacting TCR and pep-MHC binding surfaces. Sec- that binding-induced self-association is not a general ond, following crystallographic analysis of only a handful feature of TCR/pep-MHC interactions and is therefore of pep-MHC complexes it is already clear that the orien- unlikely to be the mechanism of TCR triggering. tation in which different TCRs engage pep-MHCs, al- Conformational change models typically propose though constrained to a certain extent, is quite variable that, upon binding to pep-MHC, a TCR undergoes a (Garcia et al., 1999; Hennecke and Wiley, 2001). For conformational change that is somehow transmitted to example, the angle of engagement measured around the associated CD3 signaling machinery. The difficulty the long axis of the TCR/pep-MHC complexes studied with these models is that they require, implausibly, that there is a conformational …