Journal of clinical investigation, 7 September, 2021, DOI：https://doi.org/10.1172/JCI148568
CD146 bound to LCK promotes TCR signaling and anti-tumor immune response in mice
Hongxia Duan, Lin Jing, Xiaoqing Jiang, Yanbin Ma, Daji Wang, Jianquan Xiang, Xuehui Chen, Zhenzhen Wu, Huiwen Yan, Junying Jia, Zheng Liu, Jing Feng, Mingzhao Zhu, and Xiyun Yan
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, CD146 was found 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 anti-tumor response of T cells. Together, our data reveal a previously unrecognized LCK activation mechanism for TCR initiation. We also underscore a rational intervention based on CD146 for tumor immunotherapy.