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

Abstract

The Eph and ephrin families are involved in numerous developmental processes. Recently, an increasing body of evidence has related these families with some aspects of T cell development. In the present study, we show that the addition of either EphB2-Fc or ephrinB1-Fc fusion proteins to fetal thymus organ cultures established from 17-dayold fetal mice decreases the numbers of both double-positive (CD4 + CD8 + ) and singlepositive (both CD4 + CD8 -and CD4 -CD8 + ) thymocytes, in correlation with increased apoptosis. By using reaggregate thymus organ cultures formed by fetal thymic epithelial cells (TEC) and CD4 + CD8 + thymocytes, we have also demonstrated that ephrinB1-Fc proteins are able to disorganize the three-dimensional epithelial network that in vivo supports the T cell maturation, and to alter the thymocyte interactions. In addition, in an in vitro model, Eph/ephrinB-Fc treatment also decreases the formation of cell conjugates by CD4 + CD8 + thymocytes and TEC as well as the TCR-dependent signaling between both cell types. Finally, immobilized EphB2-Fc and ephrinB1-Fc modulate the anti-CD3 antibody-induced apoptosis of CD4 + CD8 + thymocytes in a process dependent on concentration. These results therefore support a role for Eph/ephrinB in the processes of development and selection of thymocytes as well as in the establishment of the three-dimensional organization of TEC.

Ephrin-B–Dependent Thymic Epithelial Cell–Thymocyte Interactions Are Necessary for Correct T Cell Differentiation and Thymus Histology Organization: Relevance for Thymic Cortex Development

“…However, several data support a direct role of both ephrin-B1 and -B2 expressed by TECs on T cell development. Both ephrin-Bs are expressed by mature TECs (12), and published results reveal that EphB2 and/ or EphB3 forward signaling on thymocytes that depend on signals provided by TECs modulate DP T-TEC adhesion, T cell development, and TCR stimulation (14,45). Therefore, our current results on the effects of TEC-conditioned mutations on adult T cell development can be interpreted as the sum of a direct role plus the indirect consequence of an altered TEC maturation.…”

A novel feedback mechanism by Ephrin‐B1/B2 in T‐cell activation involves a concentration‐dependent switch from costimulation to inhibition

“…Recently, Hansen et al elegantly demonstrated that ephrin-As induced the biphasic retinal axon growth [21]. Alfaro et al [7] demonstrated that immobilized Eph-B2-Fc and ephrin-B1-Fc modulated the anti-CD3 antibody-induced apoptosis of CD4 + CD8…”

“…In mammals, there are nine EphAs that bind to five ephrin-As, and five EphBs (B1, B2, B3, B4, B6) that bind to three ephrin-Bs (B1, B2, B3 [2,5,6], their physiological role in immune responses are still not known. Studies have shown that a deficiency of certain Ephs leads to a defect in thymocyte maturation because of abnormal development of the stromal cells [7][8][9][10]. The effects of Eph receptors expressed on mature T cells have been reported, such as modulation of chemotaxis by certain ephrin-As and ephrin-Bs [11][12][13][14].…”

Regulation of immune cell responses by semaphorins and their receptors

“…81 In addition, it has been shown that some chemorepellent molecules, including semaphorins and ephrins, affect thymocyte differentiation during their development. [82][83][84] Sema3E, which interacts with plexin-D1 in an NP-1-independent manner, was recently reported to participate in thymocyte development. 82 Plexin-D1 expression is high in CD4 1 CD8 1 thymocytes (double-positive, DP) but decreased in single-positive cells.…”