Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses

J Immunol. 2011 Aug 1;187(3):1440-7. doi: 10.4049/jimmunol.1100820. Epub 2011 Jun 24.

Abstract

The CXCR4 chemokine receptor is a G protein-coupled receptor that signals in T lymphocytes by forming a heterodimer with the TCR. CXCR4 and TCR functions are consequently highly cross regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAPK and downstream AP-1-dependent cytokine transcription in response to stromal cell-derived factor-1 (SDF-1), the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate G protein-coupled receptor-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. In this study, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-β3 to activate the Ras-ERK pathway and increase intracellular calcium ion concentrations, whereas PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1-mediated migration via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors to distinctly regulate migration versus other signaling functions.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium Signaling / immunology
  • Cell Movement / immunology
  • Chemokine CXCL12 / physiology*
  • Endocytosis / immunology
  • Humans
  • Intracellular Fluid / enzymology
  • Intracellular Fluid / immunology
  • Isoenzymes / physiology
  • Jurkat Cells
  • MAP Kinase Signaling System / immunology
  • Phospholipase C beta / physiology*
  • Phospholipase C gamma / physiology*
  • Protein Multimerization / immunology*
  • Receptors, Antigen, T-Cell / physiology*
  • Receptors, CXCR4 / metabolism
  • Receptors, CXCR4 / physiology*
  • Signal Transduction / immunology*
  • T-Lymphocyte Subsets / enzymology
  • T-Lymphocyte Subsets / immunology*

Substances

  • CXCR4 protein, human
  • Chemokine CXCL12
  • Isoenzymes
  • Receptors, Antigen, T-Cell
  • Receptors, CXCR4
  • Phospholipase C beta
  • Phospholipase C gamma