Developing T-cell migration: role of semaphorins and ephrins.

Cell migration is a crucial event for normal T-cell development, and various ligand/receptor pairs have been implicated. Most of them, including chemokines and extracellular matrix proteins, have attractant properties on thymocytes. We discuss herein two further groups of ligand/receptor pairs, semaphorins/neuropilins and ephs/ephrins, which are constitutively expressed by thymocytes and thymic microenvironmental cells. Evidence shows that the corresponding interactions are relevant for developing T-cell migration, including the entry of bone marrow progenitor cells, migration of CD4/CD8-defined thymocyte subpopulations triggered by chemokines and/or extracellular matrix proteins, and thymocyte export. Conceptually, the data summarized here show that thymocyte migration results from a complex network of molecular interactions, which generate not only attraction, but also repulsion of migrating T-cell precursors.

Eph/Ephrin-mediated interactions in the thymus.

In the present study, we review available information on the relevance of Eph and ephrins in numerous processes occurring in the thymus that regulate not only T cell differentiation but also thymic epithelial cell (TEC) development and organization. Eph/ephrins are a large family of receptors and ligands involved in organogenesis and homeostasis of adult tissues. They are extensively expressed in the thymus and seem to be involved in the colonization of lymphoid progenitor cells and their migration throughout the thymic parenchyma necessary to provide an adequate topological location of developing thymocytes in the epithelial network that ensures their correct differentiation. In addition, EphB2 and EphB3 play a cell-autonomous role in regulating the transitions of double-negative to double-positive cells and of double-positive to single-positive thymocytes and the lack of these molecules or their ligands ephrin B1 and ephrin B2 induces profound alterations of the TEC maturation and in the arrangement of epithelial network. We emphasize that these results are largely reflecting the role played by this family of molecules in controlling thymocyte-TEC interactions within the thymus.

Eph/ephrin signaling in cancer: intricate, puzzling and ... fascinating!

The Eph receptor tyrosine kinases family and their membrane bound ligands, the ephrins, represents a complex signaling network of cell communication for cell sorting during tissue patterning in development and in the normal physiology and homeostasis of adult tissues. This molecular family has adapted to evolving tissue complexity in multicellular organisms through the emergence of more members and complex mechanisms of expression and signaling that result in the fine-tuning of cell positioning. Since their initial identification from an erythropoietin producing hepatocellular (Eph) carcinoma cell line in 1987, Eph/ephrin signaling has been a matter of intensive investigation for their plausible role in cancer. Similarly to their context dependent modus operandi in normal tissues, Eph/ephrin signaling in cancer is an intricate and puzzling network of events that tumors "manage" to their benefit in multiple aspects like cell adhesion to substrate, migration, invasion or growth.