CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses 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, Xiyun Yan
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, Xiyun Yan
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Research Article Cell biology Immunology

CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses in mice

Abstract

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.

Authors

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, Xiyun Yan

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Figure 2

CD146 is required for β selection.

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CD146 is required for β selection. (A) Left: Surface staining of CD44 an...
(A) Left: Surface staining of CD44 and CD25 on DN thymocytes from WT, CD146LCK-KO, or CD146CD4-KO mice. Middle: Schematic diagram of the left graph. Right: Percentages of DN1–DN4 subpopulations (n = 5). Numbers adjacent to outlined areas indicate percent cells in each gate. (B) Left: Intracellular staining of TCRβ in DN or DN3 cells. Right: Percentages of intracellular TCRβ+ (icTCRβ+) cells among DN or DN3 cells (n = 5). (C) Left: Intracellular staining of BrdU in CD25–icTCRβ+ and CD25+icTCRβ+ cells. Right: Percentages of BrdU+ cells in each subpopulation. Numbers adjacent to graph lines indicate the percentage of cells in each gate (n = 5). (D and E) MFI of CD69 (D) and CD5 (E) in DN3 (n = 5). (F) Left: Surface staining of TCRγδ in thymocytes from CD146LCK-WT and CD146LCK-KO mice. Right: Percentages of γδ T cells. Numbers in the outlined areas indicate percent cells in each gate (n = 5). Each symbol represents an individual mouse; the short horizontal lines indicate the mean ± SEM. One-way ANOVA followed by Bonferroni’s correction (A–C) or 2-tailed t test (D–F) was performed. **P < 0.01, ***P < 0.001.