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


CONCLUSIONS
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.
Ngai
Jacob
J
The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway. jacob.ngai@biotek.uio.no
Inngjerdingen
Marit
M
Berge
Torunn
T
Taskén
Kjetil
K
D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D025461:Feedback, Physiological; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000235:genetics; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D051960:GTP-Binding Protein alpha Subunit, Gi2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11