Interplay between the heterotrimeric G-protein subunits Gαq and Gαi2 sets the threshold for chemotaxis and TCR activation

Jacob Ngai,Torunn Berge,Kjetil Taskén,Marit Inngjerdingen

doi:10.1186/1471-2172-10-27

Abstract

BackgroundTCR 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 Gαq and Gαi2 have been implicated in CXCR4-signaling and we have recently also reported the possible involvement of Gαq in TCR-dependent activation of Lck (Ngai et al., Eur. J. Immunol., 2008, 38: 32083218). Here we examined the role of Gαq in migration and TCR activation.ResultsPre-treatment of T cells with CXCL12 led to significantly reduced Lck Y394 phosphorylation upon TCR triggering indicating heterologous desensitization. We show that knockdown of Gαq significantly enhanced basal migration in T cells and reduced CXCL12-induced SHP-1 phosphorylation whereas Gαi2 knockdown inhibited CXCL12-induced migration.ConclusionOur data suggest that Gαi2 confers migration signals in the presence of CXCL12 whereas Gαq exerts a tonic inhibition on both basal and stimulated migrational responses. This is compatible with the notion that the level of Gαq activation contributes to determining the commitment of the T cell either to migration or activation through the TCR.

Highlights

T cell receptor (TCR) and CXCR4-mediated signaling appears to be reciprocally regulated pathways
While the TCR is not thought to be directly associated with G proteins, the chemokine receptor CXCR4 can couple to both Gαq and Gαi2
SF(AiiRg)NuJuArrek(aG2tN(TseAeQgpT1re1cv0eio3lulsMswp3ea)rge)transfected with Gαq-specific siRNA (GNAQ1103), Gαi2-specific siRNA (GNAI-2-1050) or control Gαq and Gαi2 have opposing roles in chemotaxis. (A) Jurkat TAg T cells were transfected with Gαq-specific siRNA (GNAQ1103), Gαi2-specific siRNA (GNAI-2-1050) or control siRNA (GNAQ1103 M3). 48 hours post-transfection cells were placed in Costar Transwell wells with/without 10 ng/ml CXCL12

Summary

Introduction

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 Gαq and Gαi have been implicated in CXCR4-signaling and we have recently reported the possible involvement of Gαq in TCR-dependent activation of Lck The chemokine CXCL12, known as stromal cell-derived factor-1α (SDF-1α), is a member of the CXC chemokine subfamily and serves as the only known ligand for the chemokine receptor CXCR4 expressed on most leukocytes [1,2,3]. The CXCR4 receptor is a G-protein coupled receptor (GPCR) and couples to heterotrimeric G-proteins of both the Gαi and Gαq-families [6,7,8]. Members of the Gαi-family of G-proteins are pertussis toxin sensitive and pre-treatment of cells with pertussis toxin severely attenuates chemotaxis in response to chemokines. Gαi-proteins are thought to be essential for chemokine-mediated migration. Gαi3-/- mice are without phenotype [10] whereas Gαi2-/- mice display dysfunctional (page number not for citation purposes)

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