School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea.
Immune Synapse and Cell Therapy Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, South Korea.
Front Immunol. 2021 Feb 1;11:591054. doi: 10.3389/fimmu.2020.591054. eCollection 2020.
A robust T-cell response is an important component of sustained antitumor immunity. In this respect, the avidity of TCR in the antigen-targeting of tumors is crucial for the quality of the T-cell response. This study reports that the transmembrane (TM) domain of immunoglobulin superfamily member 4 (IGSF4) binds to the TM of the CD3 ζ-chain through an interaction between His177 and Asp36, which results in IGSF4-CD3 ζ dimers. IGSF4 also forms homo-dimers through the GxxVA motif in the TM domain, thereby constituting large TCR clusters. Overexpression of IGSF4 lacking the extracellular (IG4ΔEXT) domain potentiates the CD8 T cells to release IFN-γ and TNF-α and to kill OVA-B16F10 melanoma cells. In animal models, IG4ΔEXT significantly reduces B16F10 tumor metastasis as well as tumor growth. Collectively, the results indicate that the TM domain of IGSF4 can regulate TCR avidity, and they further demonstrate that TCR avidity regulation is critical for improving the antitumor activity of cytotoxic T cells.
T 细胞应答的强大是持续抗肿瘤免疫的重要组成部分。在这方面，TCR 在肿瘤抗原靶向中的亲合力对于 T 细胞应答的质量至关重要。本研究报告称，免疫球蛋白超家族成员 4（IGSF4）的跨膜（TM）结构域通过 His177 和 Asp36 之间的相互作用与 CD3 ζ 链的 TM 结合，导致 IGSF4-CD3 ζ 二聚体。IGSF4 还通过 TM 结构域中的 GxxVA 基序形成同源二聚体，从而构成大型 TCR 簇。过表达缺失细胞外（IG4ΔEXT）结构域的 IGSF4 可增强 CD8 T 细胞释放 IFN-γ 和 TNF-α 并杀死 OVA-B16F10 黑色素瘤细胞。在动物模型中，IG4ΔEXT 显著减少 B16F10 肿瘤转移和肿瘤生长。总的来说，这些结果表明 IGSF4 的 TM 结构域可以调节 TCR 亲合力，并且进一步证明 TCR 亲合力调节对于提高细胞毒性 T 细胞的抗肿瘤活性至关重要。
