Eph/Ephrin-Mediated Interactions in the Thymus

Abstract

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/ephrinB signalling is involved in the survival of thymic epithelial cells

“…In summary, these results support a role for Eph/ephrinB in the control of TEC survival, adding new functions for these molecules in the thymus glands, apart from those reported previously, 19 such as their involvement in the lymphoid colonization of the thymic primordium, the migration of thymocytes throughout distinct thymic territories, the regulation of keratin expression by TECs and the organization of thymic cortex and medulla. Taken together, these data show that Eph/ephrins are a particularly important family of molecules in thymus gland biology.…”

“…By contrast, reduced proliferation in colon crypts in mice lacking EphB2 and EphB3 does not course with an increased number of dying cells and the apoptotic cell death in crypts was not significantly affected by the inhibition of EphB signalling in ephrinB2‐Fc‐injected mice 13 . It is important to remark that some authors have reported no thymus phenotypes in mice deficient in different Eph and ephrins 19 . Particularly important for the scope of this study is the recently reported lack of alterations in the thymus of mice, which show the specific deletion of ephrinB2 in interleukin‐7‐producing TECs 31 .…”

“…The thymuses of EphB2‐ and/or EphB3‐deficient mice show profound hypocellularity that affects both thymocytes and TECs 14 , 18 . In previous studies, we have shown that reduced numbers of thymocytes in these mutants correlated with increased apoptosis, decreased numbers of cycling cells 18 and a certain capacity of bone marrow cell progenitors to colonize the thymic primordium 19 . However, the reason for the decrease in TEC numbers, evidenced from early ontogeny, 14 had not been examined.…”

Regulation of cell differentiation by Eph receptor and ephrin signaling

“…22,23 Similar considerations apply to roles of Eph-ephrin signaling in thymocyte development, in which the progression of differentiation is linked to migration through thymic stroma where they interact with thymic epithelial cells. [24][25][26] Evidence that Eph-ephrin signaling directly regulates cell differentiation has been obtained by several strategies, including in vivo studies in which cell positioning is not altered, or by identifying the intracellular pathway(s) that links Eph-ephrin activation to the regulation of gene expression. Another valuable approach comes from using unclustered or clustered Eph-Fc/ephrin-Fc fusion proteins as blocking or activating reagents, respectively, in in vitro cell culture; a caveat to some such studies is that dimeric Fc fusions can induce weak activation rather than block 27,28 and that clustered Fc proteins can activate a different signaling response from membrane-bound ligand.…”

Editorial: Ephs, ephrins, and early T cell development

“…Recent reports suggest that Eph-ephrin signaling is critical for development of a functional thymic microenvironment [9]. As Ephs and ephrins are widely expressed, the authors tested the hypothesis that stromal cells deficient in Eph-ephrin signaling might also influence progenitor seeding of the thymus.…”