CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses in mice
Hongxia Duan, … , Mingzhao Zhu, Xiyun Yan
Hongxia Duan, … , Mingzhao Zhu, Xiyun Yan
Published September 7, 2021
Citation Information: J Clin Invest. 2021;131(21):e148568. https://doi.org/10.1172/JCI148568.
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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 1

Deletion of CD146 on thymocytes inhibits T cell development.

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Deletion of CD146 on thymocytes inhibits T cell development. (A) Surface...
(A) Surface staining of CD146 (antibody clone AA1) on total thymocytes. (B) Left: Surface staining of CD146 on DN, DP, CD4+CD8int, and SP cells. Right: MFI of CD146 on DN, DP, CD4+, and CD8+ subpopulations of thymocytes from CD146WT mice (n = 5). (C) Left: Surface staining of CD146 on DN1–DN4 cells. Right: MFI of CD146 on DN1–DN4 cells (n = 5). (D) Thymus sections from CD146LCK-WT (n = 5), CD146LCK-KO (n = 5), and CD146CD4-KO mice (n = 3), stained with H&E; the darker area constitutes the cortex (C), and the lighter area constitutes the medulla (M). Original magnification, ×4. Scale bars: 1 mm. (E) Ratio of areas of M and C. (F) Total cell numbers in thymuses from WT (n = 7), CD146LCK-KO (n = 6), and CD146CD4-KO (n = 6) mice. (G) Left: Surface staining of CD4 and CD8 on thymocytes. Right: Percentages of DN, DP, and SP subpopulations (n = 5). (H) Cell numbers of DN, DP, CD4+, and CD8+ subpopulations (n = 7 for WT or 6 for KO). Each symbol represents an individual mouse; the short horizontal lines indicate the mean ± SEM. One-way ANOVA followed by Bonferroni’s correction was performed (B, C, and E–H). *P < 0.05, **P < 0.01, ***P < 0.001.