Interplay between the heterotrimeric G-protein subunits Galphaq and Galphai2 sets the threshold for chemotaxis and TCR activation

BMC Immunol. 2009 May 8;10:27. doi: 10.1186/1471-2172-10-27.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemokine CXCL12 / metabolism
  • Chemotaxis / immunology
  • Feedback, Physiological*
  • GTP-Binding Protein alpha Subunit, Gi2 / genetics
  • GTP-Binding Protein alpha Subunit, Gi2 / immunology
  • GTP-Binding Protein alpha Subunit, Gi2 / metabolism*
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / immunology
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism*
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • RNA, Small Interfering / genetics
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, CXCR4 / immunology
  • Receptors, CXCR4 / metabolism
  • Signal Transduction
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • CXCR4 protein, human
  • Chemokine CXCL12
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • Receptors, CXCR4
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • GTP-Binding Protein alpha Subunit, Gi2
  • GTP-Binding Protein alpha Subunits, Gq-G11