title: Stromal cell-derived factor-1 signaling via the CXCR4-TCR heterodimer requires phospholipase C-β3 and phospholipase C-γ1 for distinct cellular responses.
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.
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Kremer
authors.forename: Ian C
authors.initials: IC
authors.lastname: Clift
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Miamen
authors.forename: Adebowale O
authors.initials: AO
authors.lastname: Bamidele
authors.forename: Nan-Xin
authors.initials: NX
authors.lastname: Qian
authors.forename: Troy D
authors.initials: TD
authors.lastname: Humphreys
authors.forename: Karen E
authors.initials: KE
authors.lastname: Hedin
mesh_terms: D020013:Calcium Signaling / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054377:Chemokine CXCL12 / Q000502:physiology*; D004705:Endocytosis / Q000276:immunology; D006801:Humans; D007424:Intracellular Fluid / Q000201:enzymology / Q000276:immunology; D007527:Isoenzymes / Q000502:physiology; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000276:immunology; D054799:Phospholipase C beta / Q000502:physiology*; D051966:Phospholipase C gamma / Q000502:physiology*; D055503:Protein Multimerization / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology*
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D007527:Isoenzymes; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D054799:Phospholipase C beta; D051966:Phospholipase C gamma