CXCR4 physically associates with the T cell receptor to signal in T cells.
SDF-1alpha (CXCL12) signaling via its receptor, CXCR4, stimulates T cell chemotaxis and gene expression. The ZAP-70 tyrosine kinase critically mediates SDF-1alpha-dependent migration and prolonged ERK mitogen-activated protein (MAP) kinase activation in T cells. However, the molecular mechanism by which CXCR4 or other G protein-coupled receptors activate ZAP-70 has not been characterized. Here we show that SDF-1alpha stimulates the physical association of CXCR4 and the T cell receptor (TCR) and utilizes the ZAP-70 binding ITAM domains of the TCR for signal transduction. This pathway is responsible for several of the effects of SDF-1alpha on T cells, including prolonged ERK MAP kinase activity, increased intracellular calcium ion concentrations, robust AP-1 transcriptional activity, and SDF-1alpha costimulation of cytokine secretion. These results suggest new paradigms for understanding the effects of SDF-1alpha and other chemokines on immunity.
Kumar
Ashok
A
Department of Immunology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Humphreys
Troy D
TD
Kremer
Kimberly N
KN
Bramati
Patricia S
PS
Bradfield
Lavone
L
Edgar
Contessa E
CE
Hedin
Karen E
KE
D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D037181:Lectins, C-Type; D018448:Models, Immunological; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D002118:Calcium; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016753:Interleukin-10; D007376:Interleukin-2; D037181:Lectins, C-Type; D019000:Phosphotyrosine; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D018808:Transcription Factor AP-1; D051746:ZAP-70 Protein-Tyrosine Kinase; D018631:ras Proteins; D000099192:CD69 Antigens; C515255:CXCL12 protein, human