Immune Synapse Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
J Exp Med. 2011 Nov 21;208(12):2545-60. doi: 10.1084/jem.20110853. Epub 2011 Nov 14.
Immunoglobulin superfamily member 4 (IGSF4) is a known ligand of CRTAM, a receptor expressed in activated NKT and CD8(+) T cells, but its function in T cell immunity has not been elucidated. In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) ζ-chain and enhances TCR signaling by enhancing ζ-chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR ζ-chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the results indicate that IGSF4 plays a central role in T cell functioning by dual independent mechanisms, control of TCR signaling and control of T cell-APC interaction.
免疫球蛋白超家族成员 4（IGSF4）是 CRTAM 的已知配体，CRTAM 是一种在活化的 NKT 和 CD8(+)T 细胞中表达的受体，但它在 T 细胞免疫中的功能尚未阐明。在这项研究中，我们表明 IGSF4 直接与 T 细胞受体（TCR）ζ 链相互作用，并通过增强 ζ 链磷酸化增强 TCR 信号。IGSF4 的异位过表达增强了 TCR 介导的 T 细胞激活。相比之下，与对照小干扰 RNA 相比，IGSF4 敲低显示与 T 细胞激活相关的标志物显着减少。跨膜结构域对于 TCR ζ 链的关联和免疫突触的聚集至关重要，而外显子与 T 细胞与抗原呈递细胞（APC）的相互作用有关。IGSF4 缺陷小鼠的 TCR 介导的胸腺细胞选择和成熟受损。此外，这些小鼠表现出效应 T 细胞功能减弱，伴随 TCR 信号转导缺陷。总之，这些结果表明 IGSF4 通过双重独立机制在 T 细胞功能中发挥核心作用，即控制 TCR 信号和控制 T 细胞与 APC 的相互作用。
