Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity.

Eph receptors are the largest family of receptor tyrosine kinases and mediate a myriad of essential processes in humans from embryonic development to adult tissue homeostasis through interactions with membrane-bound ephrin ligands. The ubiquitous expression of Eph receptors and ephrin ligands among the cellular players of the immune system underscores the importance of these molecules in orchestrating an optimal immune response. This review provides an overview of the various roles of Eph receptors and ephrin ligands in immune cell development, activation, and migration. We also discuss the role of Eph receptors in disease pathogenesis as well as the implications of Eph receptors as future immunotherapy targets. Given the diverse and critical roles of Eph receptors and ephrin ligands throughout the immune system during both resting and activated states, this review aims to highlight the critical yet underappreciated roles of this family of signaling molecules in the immune system.

A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas.

BACKGROUND: In previous years, immunotoxins have been shown to be a greatly promising therapeutic tool for brain malignancies, such as gliomas. Human mesenchymal stem cells (hMSCs) exhibit tropism to tumor tissue. However, the effect of bispecific immunotoxins in malignant gliomas is still unknown. The aim of this study was to investigate the function of bispecific immunotoxins in human malignant gliomas. MATERIALS AND METHODS: In the present study, the bispecific immunotoxin VEGF165-ephrin A1-PE38KDEL was established using deoxyribonucleic acid shuffling and cloning techniques. The VEGF165-ephrin A1-PE38KDEL was delivered by hMSCs to mouse malignant gliomas. The effects of the bispecific immunotoxins on glioma-derived blood vessels and vasculogenic mimicry to elucidate the molecular mechanisms underlying the antitumorigenic effects of immunotoxins were examined in vivo. RESULTS: In vitro, transfected hMSCs significantly inhibited the cell viability of gliomas cell lines U87 and U251 in a dose-dependent manner compared with untransfected hMSCs (P<0.01). In vivo, the intratumoral injection of engineered hMSCs was effective at inhibiting tumor growth in a malignant glioma tumor model. CONCLUSION: The bispecific immunotoxin secreted from hMSCs acts as a novel strategy for improving treatment options for malignant gliomas in the clinic.

Effect of reduced EPHB4 expression in thymic epithelial cells on thymocyte development and peripheral T cell function.

The Eph kinase (EPH) and ephrin (EFN) families are involved in a broad range of developmental processes. Increasing evidence is demonstrating the important roles of EPHBs and EphrinBs in the immune system. In this study on epithelial cell-specific Ephb4 knockout (KO) mice, we investigated T-cell development and function after EPHB4 deletion. KO mice presented normal thymic weight and cellularity. Their thymocyte subpopulation percentages were in the normal range. KO mice had normal T-cell numbers and percentages in the spleen, and T cells were activated and proliferated normally upon TCR ligation. Furthermore, naïve spleen CD4 cells from KO and wild type mice were capable of differentiating, in a comparable manner, into Th1, Th17 and Treg cells. In vivo, KO mice mounted effective delayed type hypersensitivity responses, indicating that thymocytes develop normally in the absence of TEC EPHB4, and T cells derived from EPHB4-deleted thymic epithelian cells (TEC) have normal function. Our data suggest that heavy redundancy and promiscuous interaction between EPHs and EFNs compensate for the missing EPHB4 in TECs, and TEC EPHB4's role in T cell development might only be revealed if multiple EPHs are ablated simultaneously. We cannot exclude the possibility that (1) some immunological parameters not examined in this study are affected by the deletion; (2) the deletion is not complete due to the leaky Cre-LoxP system, and the remaining EPHB4 in TEC is sufficient for thymocyte development; or (3) EPHB4 expression in TEC is not required for T cell development and function.

A directed miniscreen for genes involved in the Drosophila anti-parasitoid immune response.

Drosophila larvae react against eggs from the endoparasitoid wasp Leptopilina boulardi by surrounding them in a multilayered cellular capsule. Once a wasp egg is recognized as foreign, circulating macrophage-like cells, known as plasmatocytes, adhere to the invader. After spreading around the wasp egg, plasmatocytes form cellular junctions between the cells, effectively separating the egg from the hemocoel. Next, a second sub-type of circulating immunosurveillance cell (hemocyte), known as lamellocytes, adhere to either the wasp egg or more likely the plasmatocytes surrounding the egg. From these events, it is obvious that adhesion and cell shape change are an essential part of Drosophila's cellular immune response against parasitoid wasp eggs. To date, very few genes have been described as being necessary for a proper anti-parasitization response in Drosophila. With this in mind, we performed a directed genetic miniscreen to discover new genes required for this response. Many of the genes with an encapsulation defect have mammalian homologues involved in cellular adhesion, wound healing, and thrombosis, including extracellular matrix proteins, cellular adhesion molecules, and small GTPases.

Eph and ephrin: Key molecules for the organization and function of the thymus gland

Las Eph son la mayor familia de receptores tirosina quinasa presentesen la mayoría de tipos celulares. Junto con sus ligandos, las ephrinas, lasEph participan en la organogénesis de muchos tejidos regulando numerosos procesos, como el posicionamiento y la migración celular, los cualesson claves para el correcto funcionamiento del timo, un órgano linfoide primario implicado en la maduración de las células T. En el presente trabajo,revisamos diferentes resultados sobre el papel que estas moléculas juegan en la biología del timo. La mayoría de las Eph y ephrinas se expresanen el timo adulto y fetal, tanto en los timocitos como en las células del estroma. Estas moléculas tienen un papel esencial regulando el tamaño del timo,a través del control de la supervivencia de los timocitos y de las células epiteliales tímicas (TEC). Además, estudios in vivo e in vitro demuestran quemodificaciones en la señalización de Eph y ephrinas resultan en fenotipostímicos específicos, concluyendo que dicha señalización determina finalmente tanto el patrón de maduración y diferenciación de los timocitos comoel de las TEC. El papel de Eph y ephrinas en la función del timo aparecepronto en la ontogenia. En este sentido, varios resultados apoyan su relevancia en procesos claves para la organización del órgano, tales como elreclutamiento de los progenitores linfoides al primordio tímico, el patrónde ramificación del epitelio tímico y el posicionamiento de los timocitos ylas TEC en el timo en crecimiento. Algunas de las alteraciones fenotípicasobservadas en el timo de ratones deficientes en Eph y ephrinas se observantambién en los órganos linfoides periféricos, pero no hay evidencias de unaalteración funcional en sus sistemas inmunes (AU)

Eph are the largest family of protein tyrosine kinases, which are described in most cell types. Together with their ligands, ephrins, Eph participate in the organogenesis of many tissues mediating numerous processes, such as cell positioning and cell migration, which are key for thefunctioning of the thymus: a primary lymphoid organ involved in T-cellmaturation. In the present study, we review available data on the role played by these families of molecules in the biology of the thymus gland.Most Eph and ephrin are expressed in adult and fetal thymus, frequentlyin both thymocytes and thymic stromal cells. They appear to play an essential role in governing thymus size through the control of survival of thymocytes and thymic epithelial cells (TEC). Furthermore, studies in vivoand in vitro demonstrate that altered Eph/ephrin signalling results in specific thymus phenotypes and conclude that the balance of Eph/ephrinsignals finally determine the pattern of maturation/differentiation of thymocytes and TEC. Indeed, the role of Eph/ephrin in thymus functionappears early in ontogeny. In this regard, several results emphasize theirrelevance in key processes for thymus organization, such as the recruitment of lymphoid progenitors to the thymic primordium, the branchingpattern of thymus epithelium and the positioning of thymocytes and TECin the growing gland. Some of the phenotypic alterations observed in thethymus of Eph/ephrin deficient mice are reflected in the peripheral lymphoid organs, but there is no evidence for alterations in the function of theirimmune systems (AU)

Recent advances on T-cell regulation by receptor tyrosine kinases.

PURPOSE OF REVIEW: This review summarizes recent knowledge on the role of receptor tyrosine kinases, particularly erythropoietin-producing hepatocyte kinases (Ephs), in T-cell function and development. RECENT FINDINGS: Erythropoietin-producing hepatocyte kinase function and signaling in the immune system have been recently investigated. Cross-linking some Ephs results in T-cell costimulation and reduces the response threshold of T-cell receptor activation. In vivo, T-cell-mediated responses are compromised in EphB6-/- mice. Some Ephs are shown to control T-cell migration and adhesion, as well as the integrity of lymphoid organ structure. SUMMARY: Ephs are the largest family of receptor tyrosine kinases. Some Ephs are expressed in the lymphoid organs. Ephrins, ligands of Ephs, are also cell surface molecules. Cross-linking of certain Ephs facilitates T-cell activation and proliferation. Under physiologic conditions, such cross-linking by ephrins likely occurs in lymphoid organs, where ephrins on T cells interact with ephrins on the surface of neighboring fraternal T cells or antigen-presenting cells; this may explain why T-cell responses are more effectively initiated in the lymphoid organs. Certain Ephs are also critical for lymphocyte adhesion and migration and for proper lymphoid organ structure. Ephs and ephrins are highly redundant and their interactions promiscuous, suggesting pivotal roles of these molecules in biology. Conversely, such redundancy represents a major challenge to further dissection of the function of individual Ephs. Multiple tissue-specific gene null mutations on Ephs or ephrins will likely reveal more interesting immune-related phenotypes.