Nature:利用人工重构系统研究T细胞受体功能

6月27日，Nature杂志在线报道了，利用人工重建反应系统研究T细胞受体介导的T-细胞免疫反应的最新进展。

T-细胞介导的免疫反应由T细胞受体（TCR）与感染细胞表面的肽结合主要组织相容性复合体（pMHC）的相互作用发起。这种相互作用T细胞受体的触发细胞内磷酸化。但是因为T细胞受体缺乏激酶结构域，使得这种磷酸化的机制更加扑朔迷离。

本研究将T细胞受体及相关信号分子引入非免疫细胞中，由此在这些细胞与抗原提呈细胞结合时，重建了配体特异性信号。研究表明，这种配体特异性信号需要磷酸酶和激酶在细胞膜上隔离开来。一个人工的，化学控制的受体系统可产生与TCR - pMHC系统同样的效果。这表明胞外蛋白质相互作用的结合能在无跨膜构象变化的条件下造成膜蛋白的空间隔离。

这种普适机制可能扩展到其他依赖于外在的激酶的受体，包括正在开发的用于肿瘤免疫治疗的嵌合抗原受体。

这一研究对于深入了解T细胞免疫反应的基本机制，以及开发更有效的免疫治疗试剂都具有重要的意义。

doi:10.1016/j.cell.2011.10.017
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Biophysical mechanism of T-cell receptor triggering in a reconstituted system

John R. James1 & Ronald D. Vale1

A T-cell-mediated immune response is initiated by the T-cell receptor (TCR) interacting with peptide-bound major histocompatibility complex (pMHC) on an infected cell. The mechanism by which this interaction triggers intracellular phosphorylation of the TCR, which lacks a kinase domain, remains poorly understood. Here, we have introduced the TCR and associated signalling molecules into a non-immune cell and reconstituted ligand-specific signalling when these cells are conjugated with antigen-presenting cells. We show that signalling requires the differential segregation of a phosphatase and kinase in the plasma membrane. An artificial, chemically controlled receptor system generates the same effect as TCR–pMHC, demonstrating that the binding energy of an extracellular protein–protein interaction can drive the spatial segregation of membrane proteins without a transmembrane conformational change. This general mechanism may extend to other receptors that rely on extrinsic kinases, including, as we demonstrate, chimaeric antigen receptors being developed for cancer immunotherapy.