CXCR4 physically associates with the T cell receptor to signal in T cells

Immunity. 2006 Aug;25(2):213-24. doi: 10.1016/j.immuni.2006.06.015.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Calcium / metabolism
  • Cells, Cultured
  • Chemokine CXCL12
  • Chemokines, CXC / pharmacology
  • Enzyme Activation / drug effects
  • Humans
  • Interleukin-10 / metabolism
  • Interleukin-2 / metabolism
  • Lectins, C-Type
  • Models, Immunological
  • Phosphotyrosine / metabolism
  • Protein Binding
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, CXCR4 / immunology*
  • Signal Transduction / immunology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcriptional Activation / genetics
  • ZAP-70 Protein-Tyrosine Kinase / metabolism
  • ras Proteins / metabolism


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD69 antigen
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Interleukin-2
  • Lectins, C-Type
  • Receptors, Antigen, T-Cell
  • Receptors, CXCR4
  • Transcription Factor AP-1
  • Interleukin-10
  • Phosphotyrosine
  • ZAP-70 Protein-Tyrosine Kinase
  • ras Proteins
  • Calcium