Chemokines, or chemoattractant cytokines, regulate the activation and migration of lymphocytes, and are vital for the efficient function of the immune system. Processes from the influx of lymphocytes into sites of inflammation to the retention of haematopoietic precursors in the bone marrow, rely on directional cues provided by these proteins. Chemokines are known to act by binding to serpentine G-protein-coupled receptors, but the details of the signalling pathways by which these receptors regulate lymphocyte migration are incompletely characterized.

Work by Ottoson and colleagues in the Journal of Immunology, studying T-cell migration in response to CXCR4 chemokine receptor signalling, now shows a new role for the tyrosine kinase ZAP-70 in these pathways. The importance of ZAP-70 in T-cell receptor (TCR) signalling is well established, but this is the first time a role for this kinase in chemokine receptor signalling has been shown.

The authors studied the movement of human Jurkat T cells through fibronectin or bovine serum albumin-coated filters in response to the CXCR4-ligand CXCL12. Whereas wild-type Jurkat T cells migrated rapidly in response to a CXCL12 gradient, P116 cells (which lack expression of ZAP-70) showed a two to threefold reduced migratory response to the same dose of CXCL12. Reconstitution of P116 cells with wild-type ZAP-70 markedly enhanced the migration of these cells, but expression of a kinase-inactive form of ZAP-70 (K369R) had minimal effect, showing that this is a ZAP-70-dependent migratory process.

Activation of ZAP-70 on TCR stimulation leads to tyrosine phosphorylation of the adaptor protein Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76), which is vital for T-cell development and activation. The authors showed that CXCL12-mediated stimulation of Jurkat T cells also results in ZAP-70-dependent tyrosine phosphorylation of SLP-76. Although CXCL12-dependent migration of SLP-76-deficient Jurkat T cells was impaired, re-expression of SLP-76 in these cells did not enhance migration.

These results show for the first time a role for ZAP-70, but not SLP-76, in CXCR4 chemokine receptor signalling in human T cells. The authors conclude that ZAP-70 might represent a point of convergence between chemokine receptor and TCR signalling pathways, and they speculate that the co-stimulatory effects of CXCL12 on T-cell activation might be mediated by ZAP-70.