Alterations in the thymocyte phenotype of EphB‐deficient mice largely affect the double negative cell compartment

Alfaro, David; Múñoz, Juan José; García‐Ceca, Javier; Cejalvo, Teresa; Jiménez, Eva; Zapata, A.

doi:10.1111/j.1365-2567.2008.02828.x

Cited by 41 publications

(80 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 84%

“…Previous studies have demonstrated a relevant role for some members of this large family of molecules in different aspects of thymus biology. EphB2 and EphB3, and their ligands ephrin-B1 and -B2, are expressed on both thymocytes and TECs (12), and Eph B2 and/or EphB3 knockout mice showed an abnormal thymic development that affects mainly the epithelial component, including the cortex/medulla distribution, TEC morphology, and different epithelial-specific marker expression (13). They also showed decreased numbers of thymocytes and altered T differentiation particularly affecting the DN cell stage (12).…”

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confidence: 99%

“…EphB2 and EphB3, and their ligands ephrin-B1 and -B2, are expressed on both thymocytes and TECs (12), and Eph B2 and/or EphB3 knockout mice showed an abnormal thymic development that affects mainly the epithelial component, including the cortex/medulla distribution, TEC morphology, and different epithelial-specific marker expression (13). They also showed decreased numbers of thymocytes and altered T differentiation particularly affecting the DN cell stage (12). Studies based on chimeras revealed that these receptors play an autonomous role both in T cell differentiation and TEC development, but they also affect nonautonomously the other thymic component (14,15).…”

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confidence: 99%

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

Cejalvo

Múñoz

Tobajas

et al. 2013

The Journal of Immunology

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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.

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

Cejalvo

Múñoz

Tobajas

et al. 2013

The Journal of Immunology

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“…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].…”

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confidence: 99%

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

et al. 2012

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Bidirectional signals via Eph receptors/ephrins have been recognized as major forms of contact-dependent cell communications such as cell attraction and repulsion. T cells express EphBs, and their ligands, the ephrin-Bs, have been known as costimulatory molecules for T-cell proliferation.Recently, another remarkable feature of ephrin-As has emerged in the form of a concentration-dependent transition from promotion to inhibition in axon growth. Here we examined whether this modification plays a role in ephrin-B costimulation in murine primary T cells. Low doses of ephrin-B1 and ephrin-B2 costimulated T-cell proliferation induced by anti-CD3, but high concentrations strongly inhibited it. In contrast, ephrin-B3 showed a steadily increasing stimulatory effect. This modulation was virtually preserved in T cells from mice simultaneously lacking four genes, EphB1, EphB2, EphB3, and EphB6. High concentrations of ephrin-B1/B2, but not ephrin-B3, inhibited the anti-CD3-induced phosphorylation of Lck and its downstream signals such as Erk and Akt. Additionally, high doses of any ephrin-Bs could phosphorylate EphB4. However, only ephrin-B1/B2 but not ephrin-B3 recruited SHP1, a phosphatase to suppress the phosphorylation of Lck. These data suggest that EphB4 signaling could engage in negative feedback to TCR signals. T-cell activation may be finely adjusted by the combination and concentration of ephrin-Bs expressed in the immunological microenvironment. Keywords: Biphasic modulation · EphB · Ephrin-B · TCR Supporting Information available online IntroductionEph receptors are the largest known family of receptor tyrosine kinases (RTKs). These receptors can be classified into two groups, Correspondence: Dr. Toshimitsu Matsui e-mail: matsui.kobe@gmail.com EphAs and EphBs, based on their sequence homology. Ligands for Eph receptors, so called ephrins, are also divided into two classes. Some are membrane anchored by a glycosylphosphatidylinositol linkage (ephrin-A) and the others through a transmembrane domain (ephrin-B). 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]. Eph signaling in thymocytes has been reported to blunt the effects of high T-cell receptor (TCR) signaling [15][16][17], suggesting the possible inhibition of negative selection of self-reactive thymocytes. In contrast, Wu and colleagues have proposed promotional TCR costimulatory effects of all ephrin-Bs by using their original ephrin-B-Fc chimeric proteins [18][19][20]. However, the molecular basis for an Eph/ephrin system to inhibit or promote TCR signaling in each cell type ...

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“…The defects seen in thymocyte maturation in Eph-or ephrin-deficient thymi are thought to result from abnormal development of the stromal cell compartments (27) and modulation of T cell responses (28). For example, EphB2-and/or EphB3-deficient mice exhibit decreased numbers of thymocyte subsets (29), the lack of EphA4 expression results in hypoplastic thymi and decreased numbers of double-positive (CD4 + CD8 + ) thymocytes (27), and blocking fetal thymic organ cultures with EphB2/Fc or ephrin-B1/Fc fusion proteins decreases doublepositive and single-positive T cell populations (30).…”

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EphB–ephrin-B2 interactions are required for thymus migration during organogenesis

Foster¹,

Jack

Cardenas

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Thymus organogenesis requires coordinated interactions of multiple cell types, including neural crest (NC) cells, to orchestrate the formation, separation, and subsequent migration of the developing thymus from the third pharyngeal pouch to the thoracic cavity. The molecular mechanisms driving these processes are unclear; however, NC-derived mesenchyme has been shown to play an important role. Here, we show that, in the absence of ephrin-B2 expression on thymic NC-derived mesenchyme, the thymus remains in the cervical area instead of migrating into the thoracic cavity. Analysis of individual NC-derived thymic mesenchymal cells shows that, in the absence of ephrin-B2, their motility is impaired as a result of defective EphB receptor signaling. This implies a NC-derived cellspecific role of EphB-ephrin-B2 interactions in the collective migration of the thymic rudiment during organogenesis.T hymus development in the mouse begins at E9.5 with the formation of the third pharyngeal pouches and concomitant expression of transcription factors including Hoxa3, Pax1/9, Eya1, and Six1/4 within the third pharyngeal pouch endoderm (1-4). Soon after, neural crest (NC)-derived mesenchymal cells (NCCs) from the posterior hindbrain undergo epithelial-to-mesenchymal transition (EMT), delaminate, and migrate to and surround the pouch, which simultaneously begins to grow into a separate structure containing the thymus and parathyroid primordia. By E12.5, the thymic primordium is completely detached from both the pharyngeal pouch and parathyroid. Subsequently, the bilateral lobes descend into the thoracic cavity, where they finally settle in the upper mediastinum above the heart. NCCs, which contribute to various tissues in the mouse, are also key players in thymus organogenesis. NC-derived cells have been shown to regulate patterning of the third-pouch endoderm into thymus and parathyroid-specific domains (5) and stimulate thymic epithelial cell (TEC) proliferation and maturation through production of FGFs (6). NC-derived cells also stabilize blood-vessel structures by differentiating into perivascular cells (7,8).The mechanisms that control the various morphogenetic events during early thymus organogenesis are still largely unknown, although some genes have been identified that affect these events. Hox3 and Pax1/9 transcription factors act in a pathway that is required for proper separation and/or migration of the developing thymic and parathyroid primordia from the pharynx, although the cell-type specificity of these functions is poorly understood (2, 9, 10). Splotch embryos, which have a null allele of Pax3 and are largely deficient of NCCs, also exhibit pharyngeal-pouch defects, including an ectopic thymus (5, 11). This NCC deficiency resulted in delayed separation of the thymus and parathyroid from the pharynx, and the boundary between thymus and parathyroid-fated domains was abnormal. These results strongly implicated NCC migration to the third pharyngeal pouch in patterning and morphogenesis of the thymus and parathyroids (5...

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Alterations in the thymocyte phenotype of EphB‐deficient mice largely affect the double negative cell compartment

Cited by 41 publications

References 47 publications

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

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

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

EphB–ephrin-B2 interactions are required for thymus migration during organogenesis

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