TCR activation inhibits chemotaxis toward stromal cell-derived factor-1: evidence for reciprocal regulation between CXCR4 and the TCR.
Stromal cell-derived factor-1 (SDF-1), a C-X-C family chemokine, is a potent T lymphocyte chemoattractant. We investigated the effects of T cell activation on the chemotactic response to SDF-1. Anti-CD3 Ab stimulation of either Jurkat T cells or murine peripheral CD4+ T lymphocytes produced a dramatic inhibition of SDF-1-induced chemotaxis. In contrast, the SDF-1 responses of Jurkat clones with deficiencies in key TCR signaling components (Lck, CD45, and TCR-beta), were only marginally reduced by anti-CD3 stimulation. Similar to PMA treatment, which abolished both CXCR4 receptor expression and the chemotactic response of Jurkat cells to SDF-1, anti-CD3 Ab treatment reduced cell surface expression of CXCR4 to 65% of the control value, an effect that was blocked by protein kinase C inhibitors. Our data suggest that initial T cell activation events inhibit the response of Jurkat T cells to CXCR4 stimulation. In contrast, SDF-1 treatment resulted in a reduction of tyrosine phosphorylation of the TCR downstream effectors, ZAP-70, SLP-76, and LAT (linker for activation of T cells), suggesting that this chemokine potentially regulates the threshold for T cell activation.
Peacock
J W
JW
Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada.
Jirik
F R
FR
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008970:Molecular Weight; D016853:Muromonab-CD3 / Q000494:pharmacology; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism* / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C515255:CXCL12 protein, human; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C110810:LAT protein, human; C491734:Lat protein, mouse; D008565:Membrane Proteins; D016853:Muromonab-CD3; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; C092947:SLP-76 signal Transducing adaptor proteins; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate