Do inhibitory receptors need to be proximal to stimulatory receptors to function?
Do inhibitory receptors need to be proximal to stimulatory receptors to function?
复制标题
抑制性受体是否需要靠近刺激性受体才能发挥作用？
DOI：
10.1038/s41435-023-00251-6
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发表时间：
2024
影响因子：
5
通讯作者：
Worboys JD
中科院分区：
文献类型：
--
作者：
Worboys JD
我们最近证明了具有IG和ITIM结构域的抑制性受体T细胞免疫受体（TIGIT）在与其配体CD 155连接后在T细胞表面组装成纳米级簇。至关重要的是，这些富含TIGIT的纳米簇与T细胞受体（TCR）纳米簇共定位[1]，同时降低效应子功能，例如超抗原刺激后细胞因子IL-2的产生。具有阻止抑制信号经由其ITT样和ITIM结构域转导的突变的TIGIT在与⑶ 155连接后仍然聚集并定位于TCR簇，但不能抑制功能结果。因此，定位于TCR的抑制性TIGIT信号传导导致较少的细胞活化。问题来了：抑制性受体和刺激性受体（如TIGIT和TCR）的纳米级接近对于抑制功能是必不可少的吗？抑制性受体与刺激性受体的接近对于功能性抑制可能是重要的，这主要有两种方式：（i）抑制性受体起作用以破坏局部刺激性受体信号传导，和/或（ii）抑制性受体需要来自刺激性受体的信号来刺激自身。在这里，我们提供了支持这些观点的抑制性受体PD-1，CTLA-4和LAG 3的例子（总结在图1中）。
We recently demonstrated that the inhibitory receptor T cell immunoreceptor with Ig and ITIM domains (TIGIT) assembles in nanoscale clusters at the T cell surface upon ligation with its ligand CD155. Crucially, these TIGIT-rich nanoclusters co-localise with T cell receptor (TCR) nanoclusters [1], concurrent with reduced effector functions, such as production of the cytokine IL-2 upon superantigen stimulation. TIGIT with mutations that prevented transduction of inhibitory signals via its ITT-like and ITIM domains, still clustered upon ligation with CD155 and localised to TCR clusters, but could not inhibit functional outcomes. Thus, inhibitory TIGIT signalling localised to the TCR leads to less cellular activation. The question arises: is the nanoscale proximity of inhibitory and stimulatory receptors, like TIGIT and the TCR, essential for inhibitory function? There are two main ways in which proximity of an inhibitory receptor to a stimulatory receptor could be important for functional inhibition:(i) Inhibitory receptors act to disrupt local stimulatory receptor signalling, and/or (ii) Inhibitory receptors require signals from stimulatory receptors to be stimulated themselves. Here, we provide examples with the inhibitory receptors PD-1, CTLA-4 and LAG3 that support each of these views (summarised in Fig. 1).
影响因子：
2.9
作者：
Bradshaw, JD;Lu, P;Kurtz, SE
通讯作者：
Kurtz, SE
影响因子：
32.4
作者：
Egen, JG;Allison, JP
通讯作者：
Allison, JP