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Vav1-phospholipase C-?1 (Vav1-PLC-?1) pathway initiated by T cell antigen receptor (TCR??) activation is required to overcome inhibition by ubiquitin ligase Cbl-b during ??T cell cytotoxicity.


ABSTRACT: T cell antigen receptor ?? (TCR??) and natural killer group 2, member D (NKG2D) are two crucial receptors for ??T cell cytotoxicity. Compelling evidences suggest that ??T cell cytotoxicity is TCR??-dependent and can be co-stimulated by NKG2D. However, the molecular mechanism of underlying TCR??-dependent activation of ??T cells remains unclear. In this study we demonstrated that TCR?? but not NKG2D engagement induced lytic granule polarization and promoted ??T cell cytotoxicity. TCR?? activation alone was sufficient to trigger Vav1-dependent phospholipase C-?1 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 ??T cell cytotoxicity through the Vav1-phospholipase C-?1 pathway. Vav1 overexpression or Cbl-b knockdown not only enhanced TCR?? activation-initiated killing but also enabled NKG2D activation alone to induce ??T cell cytotoxicity. Taken together, our results suggest that the activation of ??T 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 ??T cell cytotoxicity and likely implications for optimizing ??T cell-based cancer immunotherapy.

SUBMITTER: Yin S 

PROVIDER: S-EPMC3772191 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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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.

Yin Shanshan S   Zhang Jianmin J   Mao Yujia Y   Hu Yu Y   Cui Lianxian L   Kang Ning N   He Wei W  

The Journal of biological chemistry 20130729 37


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  ...[more]

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