Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
J Clin Invest. 2021 Nov 1;131(21). doi: 10.1172/JCI148568.
Initiation of T cell receptor (TCR) signaling involves the activation of the tyrosine kinase LCK; however, it is currently unclear how LCK is recruited and activated. Here, we have identified the membrane protein CD146 as an essential member of the TCR network for LCK activation. CD146 deficiency in T cells substantially impaired thymocyte development and peripheral activation, both of which depend on TCR signaling. CD146 was found to directly interact with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain. Interestingly, we found CD146 to be present in both monomeric and dimeric forms in T cells, with the dimerized form increasing after TCR ligation. Increased dimerized CD146 recruited LCK and promoted LCK autophosphorylation. In tumor models, CD146 deficiency dramatically impaired the antitumor response of T cells. Together, our data reveal an LCK activation mechanism for TCR initiation. We also underscore a rational intervention based on CD146 for tumor immunotherapy.
T 细胞受体 (TCR) 信号的起始涉及酪氨酸激酶 LCK 的激活；然而，目前尚不清楚 LCK 如何被募集和激活。在这里，我们已经确定了膜蛋白 CD146 是 TCR 网络中 LCK 激活的必需成员。T 细胞中 CD146 的缺乏会严重损害胸腺细胞的发育和外周激活，这两者都依赖于 TCR 信号。发现 CD146 通过其细胞质结构域与无共受体的 LCK 的 SH3 结构域直接相互作用。有趣的是，我们发现 CD146 以单体和二聚体形式存在于 T 细胞中，TCR 交联后二聚体形式增加。二聚化的 CD146 募集 LCK 并促进 LCK 自身磷酸化。在肿瘤模型中，CD146 的缺乏极大地损害了 T 细胞的抗肿瘤反应。总之，我们的数据揭示了 TCR 起始的 LCK 激活机制。我们还强调了基于 CD146 的肿瘤免疫治疗的合理干预措施。
