Thymic Alterations in EphA4-Deficient Mice

Múñoz, Juan José; Alfaro, David; García‐Ceca, Javier; Alonso-C, Luis M; Jiménez, Eva; Zapata, A.

doi:10.4049/jimmunol.177.2.804

Cited by 56 publications

(77 citation statements)

References 71 publications

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“…Moreover, the expression of the different members of the family seems to be regulated, and several Ephs and ephrins appear on the same thymic cell type and at the same thymocyte developmental stage [17,18], indicating a wide plasticity that allows different combinations of signals. We have previously demonstrated a general role for the EphA subfamily in thymocyte development [16] and a more specific role for EphA4 in the thymic epithelial network organization which indirectly affected the T cell development [19]. Recent evidence of regulation of anti-CD3 antibody-induced apoptosis has also been reported [20].…”

Section: Introductionmentioning

confidence: 89%

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

et al. 2007

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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.

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Section: Introductionmentioning

confidence: 89%

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

et al. 2007

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“…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.…”

Section: Semaphorins In the Thymusmentioning

confidence: 99%

Regulation of immune cell responses by semaphorins and their receptors

2010

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Semaphorins were originally identified as axon guidance factors involved in the development of the neuronal system. However, accumulating evidence indicates that several members of semaphorins, so-called 'immune semaphorins', are crucially involved in various phases of immune responses. These semaphorins regulate both immune cell interactions and immune cell trafficking during physiological and pathological immune responses. Here, we review the following two functional aspects of semaphorins and their receptors in immune responses: their functions in cell-cell interactions and their involvement in immune cell trafficking.

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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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confidence: 99%

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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Thymic Alterations in EphA4-Deficient Mice

Cited by 56 publications

References 71 publications

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

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

Regulation of immune cell responses by semaphorins and their receptors

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

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