Abstract
Background:
TCR and CXCR4-mediated signaling appears to be reciprocally regulated pathways. TCR activation dampens the chemotactic response towards the CXCR4 ligand CXCL12, while T cells exposed to CXCL12 are less prone to subsequent TCR-activation. The heterotrimeric G proteins Galphaq and Galphai2 have been implicated in CXCR4-signaling and we have recently also reported the possible involvement of Galphaq in TCR-dependent activation of Lck (Ngai et al., Eur. J. Immunol., 2008, 38: 32083218). Here we examined the role of Galphaq in migration and TCR activation.
Results:
Pre-treatment of T cells with CXCL12 led to significantly reduced Lck Y394 phosphorylation upon TCR triggering indicating heterologous desensitization. We show that knockdown of Galphaq significantly enhanced basal migration in T cells and reduced CXCL12-induced SHP-1 phosphorylation whereas Galphai2 knockdown inhibited CXCL12-induced migration.
Conclusion:
Our data suggest that Galphai2 confers migration signals in the presence of CXCL12 whereas Galphaq exerts a tonic inhibition on both basal and stimulated migrational responses. This is compatible with the notion that the level of Galphaq activation contributes to determining the commitment of the T cell either to migration or activation through the TCR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Chemokine CXCL12 / metabolism
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Chemotaxis / immunology
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Feedback, Physiological*
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GTP-Binding Protein alpha Subunit, Gi2 / genetics
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GTP-Binding Protein alpha Subunit, Gi2 / immunology
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GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
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GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
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GTP-Binding Protein alpha Subunits, Gq-G11 / immunology
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GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
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Humans
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Jurkat Cells
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Lymphocyte Activation
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
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RNA, Small Interfering / genetics
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, CXCR4 / immunology
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Receptors, CXCR4 / metabolism
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Signal Transduction
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism*
Substances
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CXCR4 protein, human
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Chemokine CXCL12
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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Receptors, CXCR4
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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GTP-Binding Protein alpha Subunit, Gi2
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GTP-Binding Protein alpha Subunits, Gq-G11