title: Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) pathway initiated by T cell antigen receptor (TCRγδ) activation is required to overcome inhibition by ubiquitin ligase Cbl-b during γδT cell cytotoxicity.
abstract: T cell antigen receptor γδ (TCRγδ) and natural killer group 2, member D (NKG2D) are two crucial receptors for γδT cell cytotoxicity. Compelling evidences suggest that γδT cell cytotoxicity is TCRγδ-dependent and can be co-stimulated by NKG2D. However, the molecular mechanism of underlying TCRγδ-dependent activation of γδT cells remains unclear. In this study we demonstrated that TCRγδ but not NKG2D engagement induced lytic granule polarization and promoted γδT cell cytotoxicity. TCRγδ activation alone was sufficient to trigger Vav1-dependent phospholipase C-γ1 signaling, resulting in lytic granule polarization and effective killing, whereas NKG2D engagement alone failed to trigger cytotoxicity-related signaling to overcome the inhibitory effect of Cbl-b; therefore, NKG2D engagement alone could not induce effective killing. However, NKG2D ligation augmented the activation of γδT cell cytotoxicity through the Vav1-phospholipase C-γ1 pathway. Vav1 overexpression or Cbl-b knockdown not only enhanced TCRγδ activation-initiated killing but also enabled NKG2D activation alone to induce γδT cell cytotoxicity. Taken together, our results suggest that the activation of γδT cell cytotoxicity requires a strong activation signal to overcome the inhibitory effect of Cbl-b. Our finding provides new insights into the molecular mechanisms underlying the initiation of γδT cell cytotoxicity and likely implications for optimizing γδT cell-based cancer immunotherapy.
authors.affiliation: From the Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Peking Union Medical College, National Key Laboratory of Medical Molecular Biology, Beijing 100005, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Yin
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
authors.forename: Yujia
authors.initials: Y
authors.lastname: Mao
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.forename: Lianxian
authors.initials: L
authors.lastname: Cui
authors.forename: Ning
authors.initials: N
authors.lastname: Kang
authors.forename: Wei
authors.initials: W
authors.lastname: He
mesh_terms: D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D051567:Proto-Oncogene Proteins c-vav; D016692:Receptors, Antigen, T-Cell, gamma-delta; C496618:VAV1 protein, human; D007371:Interferon-gamma; D050721:Proto-Oncogene Proteins c-cbl; D051966:Phospholipase C gamma; D002118:Calcium
keywords: Cancer Therapy; Cell Signaling; Innate Immunity; Phospholipase C; T Cell
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