Ephrin stimulation modulates T?cell chemotaxis

Abstract

Eph receptor tyrosine kinases and their ligands, the ephrins, are known to play an important role in regulating cell migration and targeting in neuronal and endothelial cells. Recently, it hasbeen shown that lymphoid cells also express Eph receptors, raising the possibility that Eph receptors may similarly regulate lymphocyte migration. Chemotaxis in response to soluble chemokine factors is an essential facet of T cell biology. We demonstrate here that T cell chemotaxis in response to both the stromal cell‐derived factor (SDF)‐1α and macrophage inflammatory protein 3β chemokines is modulated by costimulation with ephrins. Both ephrin‐A and ephrin‐B ligands were found to modify the chemotactic responses of a T cell line and primary T cells. Ephrin‐A1, in particular, strongly inhibited chemotaxis. In accordance with the tyrosine kinase activity of EphA receptors, ephrin‐A1 stimulation induced rapid intracellular tyrosine phosphorylation in T cells. Although strongly inhibiting chemotaxis, ephrin‐A1 costimulus did not affect many of the signaling events downstream of the SDF‐1α receptor CXCR4, including calcium flux and activation of MAPK. Rather, ephrin‐A1 altered the balance of small G protein activity in T cells. Ephrin‐A1 stimulation prevented SDF‐1α–induced activation of cdc42, while simultaneously inducing rho activation. Ultimately, ephrin‐A1 was found to inhibit chemokine‐induced actin polymerization, thereby blocking migration. Ubiquitous ephrin expression in vivo creates enormous potential for T cells to encounter these ligands, suggesting that Eph receptors and ephrins may be important regulators of T cell migration.

Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas

“…Eph/ephrin signaling is known to alter chemokineinduced lymphocyte chemotaxis (Sharfe et al, 2002), which prompted us to ask whether soluble EphA7 could influence B-lymphocyte chemotaxis in a transwell migration assay. To test this possibility, Nalm-6 B-cells were allowed to migrate to SDF-1a with or without preincubation with EphA7-Fc, a purified recombinant protein comprising the first 549 amino acids of the extracellular domain of EphA7.…”

Regulation of immune cell responses by semaphorins and their receptors

“…1 For example, some axon guidance molecules, such as slits [2][3][4] and ephrins, [5][6][7][8] have been shown to regulate immune cell migration. In addition, T-cell-antigenpresenting cell contact sites, the so-called 'immunological synapse', is structurally similar to the 'neurological synapse' that connects pairs of neurons.…”

EphrinB1‐EphB signaling regulates thymocyte‐epithelium interactions involved in functional T cell development

“…Recent evidence of regulation of anti-CD3 antibody-induced apoptosis has also been reported [20]. The role of the EphB subfamily in T cell development and function is largely restricted to T cell costimulation (reviewed in [21]), and both Eph families have also been reported to be involved in the regulation of lymphocyte chemotaxis [5,22].…”

“…These processes of cell positioning, cell movement and cell-to-cell interactions parallel to cell differentiation are regulated by signaling pathways, including the Eph family of tyrosine kinase receptors and their ligands, the ephrins, common or equivalent in different developmental systems. Ephs and ephrins constitute a complex system involved in regulating cell-to-cell and cell-to-extracellular matrix attachments-detachments and in chemokine-driven cell migration in different cell types [4], including thymocytes [5]. Furthermore, Eph-ephrin activation, directly or by crosstalk with other surface receptors [6], can lead to cell division [7][8][9], programmed cell death [7,10,11] or cell differentiation [12].…”