Department of Chemical and Biological Physics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Lymphocyte Cell Biology Unit, INSERM U1221, Department of Immunology, Institut Pasteur, Paris 75015, France.
Cell Rep. 2020 Mar 10;30(10):3434-3447.e6. doi: 10.1016/j.celrep.2020.02.069.
T cell surfaces are covered with microvilli, actin-rich and flexible protrusions. We use super-resolution microscopy to show that ≥90% of T cell receptor (TCR) complex molecules TCRαβ and TCRζ, as well as the co-receptor CD4 (cluster of differentiation 4) and the co-stimulatory molecule CD2, reside on microvilli of resting human T cells. Furthermore, TCR proximal signaling molecules involved in the initial stages of the immune response, including the protein tyrosine kinase Lck (lymphocyte-specific protein tyrosine kinase) and the key adaptor LAT (linker for activation of T cells), are also enriched on microvilli. Notably, phosphorylated proteins of the ERM (ezrin, radixin, and moesin) family colocalize with TCRαβ as well as with actin filaments, implying a role for one or more ERMs in linking the TCR complex to the actin cytoskeleton within microvilli. Our results establish microvilli as key signaling hubs, in which the TCR complex and its proximal signaling molecules and adaptors are preassembled prior to activation in an ERM-dependent manner, facilitating initial antigen sensing.
T 细胞表面覆盖着微绒毛，这是富含肌动蛋白且灵活的突起。我们利用超分辨率显微镜显示，在静息的人类 T 细胞中，≥90%的 T 细胞受体（TCR）复合物分子 TCRαβ 和 TCRζ，以及共受体 CD4（分化簇 4）和共刺激分子 CD2，都位于微绒毛上。此外，参与免疫反应初始阶段的 TCR 近端信号分子，包括蛋白酪氨酸激酶 Lck（淋巴细胞特异性蛋白酪氨酸激酶）和关键衔接子 LAT（T 细胞激活的衔接子），也在微绒毛上富集。值得注意的是，ERM（埃兹蛋白、radixin 和 moesin）家族的磷酸化蛋白与 TCRαβ 以及肌动蛋白丝共定位，这意味着 ERM 中的一种或多种蛋白在将 TCR 复合物以 ERM 依赖性的方式连接到微绒毛中的肌动蛋白细胞骨架中，从而在初始抗原感应中发挥作用。
我们的结果确立了微绒毛作为关键的信号枢纽，在这个信号枢纽中，TCR 复合物及其近端信号分子和衔接子以前馈的方式预先组装，从而促进初始抗原感应。
