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

Abstract

Previous analysis on the thymus of erythropoietin-producing hepatocyte kinases (Eph) B knockout mice and chimeras revealed that Eph-Eph receptor–interacting proteins (ephrins) are expressed both on T cells and thymic epithelial cells (TECs) and play a role in defining the thymus microenvironments. In the current study, we have used the Cre-LoxP system to selectively delete ephrin-B1 and/or ephrin-B2 in either thymocytes (EfnB1thy/thy, EfnB2thy/thy, and EfnB1thy/thyEfnB2thy/thy mice) or TECs (EfnB1tec/tec, EfnB2tec/tec, and EfnB1tec/tecEfnB2tec/tec mice) and determine the relevance of these Eph ligands in T cell differentiation and thymus histology. Our results indicate that ephrin-B1 and ephrin-B2 expressed on thymocytes play an autonomous role in T cell development and, expressed on TECs, their nonautonomous roles are partially overlapping. The effects of the lack of ephrin-B1 and/or ephrin-B2 on either thymocytes or TECs are more severe and specific on thymic epithelium, contribute to the cell intermingling necessary for thymus organization, and affect cortical TEC subpopulation phenotype and location. Moreover, ephrin-B1 and ephrin-B2 seem to be involved in the temporal appearance of distinct cortical TECs subsets defined by different Ly51 levels of expression on the ontogeny.

The Eph-related tyrosine kinase ligand Ephrin-B1 marks germinal center and memory precursor B cells

“…Ephrin-B1 has a critical role as a repulsive guidance cue during tissue development, and mutations in the gene result in a wide spectrum of developmental abnormalities constituting craniofrontonasal syndrome in humans and related defects in mice (Bush and Soriano, 2009). Ephrin-B1 is also important in bone formation and in thymocyte development (Xing et al, 2010; Luo et al, 2011; Cejalvo et al, 2013). To test whether Ephrin-B1 may have a functional role in GC B cell development we generated mice in which Efnb1 was specifically deleted in B cells ( Efnb1 f/f Mb1 Cre/+ ).…”

Chronic TCDD exposure results in the dysregulation of gene expression in splenic B-lymphocytes and in the impairments in T-cell and B-cell differentiation in mouse model

“…However, the molecular mechanisms linking the environmental contamination to NHL are not fully elucidated. One such link can be provided by the Eph/ephrin family of the receptor tyrosine kinases known to play critical roles in lymphocyte differentiation (Cejalvo et al, 2013;Himanen et al, 2007). Upregulation of the Ephrin signaling pathway is one commonly found marker strongly associated with the oncogenic transformation (Pasquale, 2010;Xi et al, 2012).…”

Developing stratified epithelia: lessons from the epidermis and thymus

“…EphB2 and EphB3 and their ligands ephrinB1 and ephrinB2 are expressed on both TECs and thymocytes . Conditional deletion of ephrinB1 and ephrinB2 in epithelial cells leads to alterations in skin development including short hair and premature eye opening . Furthermore, these mice exhibited abnormal thymic epithelial architecture, characterized by a reduced size and a higher proportion of K5 + K8 + presumptive thymic epithelial progenitor cells and thymic epithelial cysts .…”

“…Conditional deletion of ephrinB1 and ephrinB2 in epithelial cells leads to alterations in skin development including short hair and premature eye opening . Furthermore, these mice exhibited abnormal thymic epithelial architecture, characterized by a reduced size and a higher proportion of K5 + K8 + presumptive thymic epithelial progenitor cells and thymic epithelial cysts . Since EphA4 can bind to ephrinB ligands, it is possible that some of the thymic phenotypes in the ephrinB1/B2 and EphA4 null mice may be shared.…”

“…Eph receptors, which bind to membrane bound ephrins, represent the largest group of receptor tyrosine kinases in mammals. 111,112 Ephs are classified into two subfamilies, EphA and EphB, depending on their binding preference to glycosylphophatidylinositol (GPI)-anchored ephrins A or transmembrane ephrins B ligands, respectively. 111,113 In both the epidermis and thymus, Eph receptors and ephrins are compartmentalized with differential expression in distinct cell subsets.…”