Cutting Edge: Thymic Crosstalk Regulates Delta-Like 4 Expression on Cortical Epithelial Cells

Fiorini, Emma; Ferrero, Isabel; Merck, Estelle; Favre, Stéphanie; Pierres, Michel; Luther, Sanjiv A.; MacDonald, H. Robson

doi:10.4049/jimmunol.181.12.8199

Cited by 65 publications

(67 citation statements)

References 22 publications

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“…A heterogeneity within the cortical microenvironment is suggested to exist on the basis of the differential expression of CD205, Ly51, IL-7, Dll4, b5t, and CCRL1 (17,18,22,26,34,35). Our kinetic analysis during thymic ontogeny revealed that Il7…”

Section: Discussionmentioning

confidence: 91%

“…These findings have raised the hypothesis that lymphoepithelial interactions affect the size and function of cortical epithelial microenvironments while promoting mTEC diversification (17)(18)(19) (20) and Marilyn-Rag2 2/2 (21) C57BL/6 background. Dual reporter mice were generated by crossing IL-7 reporter mice with Ccrl1: eGFP reporter mice (CCRL1-reporter) (22).…”

Section: Il2rgmentioning

confidence: 99%

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Thymocyte Selection Regulates the Homeostasis of IL-7–Expressing Thymic Cortical Epithelial Cells In Vivo

Ribeiro

Rodrigues

Meireles

et al. 2013

The Journal of Immunology

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Thymic epithelial cells (TECs) help orchestrate thymopoiesis, and TEC differentiation relies on bidirectional interactions with thymocytes. Although the molecular mediators that stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals that regulate cortical thymic epithelial cell (cTEC) homeostasis remain elusive. Using IL-7 reporter mice, we show that TECs coexpressing high levels of IL-7 (Il7YFP+ TECs) reside within a subset of CD205+Ly51+CD40low cTECs that coexpresses Dll4, Ccl25, Ccrl1, Ctsl, Psmb11, and Prss16 and segregates from CD80+CD40high mTECs expressing Tnfrsf11a, Ctss, and Aire. As the frequency of Il7YFP+ TECs gradually declines as mTEC development unfolds, we explored the relationship between Il7YFP+ TECs and mTECs. In thymic organotypic cultures, the thymocyte-induced reduction in Il7YFP+ TECs dissociates from the receptor activator of NF-κB–mediated differentiation of CD80+ mTECs. Still, Il7YFP+ TECs can generate some CD80+ mTECs in a stepwise differentiation process via YFP−Ly51lowCD80low intermediates. Il7YFP+ TECs are sustained in Rag2−/− mice, even following in vivo anti-CD3ε treatment that mimics the process of pre-TCR β-selection of thymocytes to the double positive (DP) stage. Using Marilyn-Rag2−/− TCR transgenic, we find that positive selection into the CD4 lineage moderately reduces the frequency of Il7YFP+ TECs, whereas negative selection provokes a striking loss of Il7YFP+ TECs. These results imply that the strength of MHC/peptide–TCR interactions between TECs and thymocytes during selection constitutes a novel rheostat that controls the maintenance of IL-7–expressing cTECs.

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Section: Discussionmentioning

confidence: 91%

Section: Il2rgmentioning

confidence: 99%

Thymocyte Selection Regulates the Homeostasis of IL-7–Expressing Thymic Cortical Epithelial Cells In Vivo

Ribeiro

Rodrigues

Meireles

et al. 2013

The Journal of Immunology

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“…10,11,29,47 Data from several reports support the notion that thymocytes supply "crosstalk" signals to support TEC development in both mice and humans. [48][49][50][51][52][53] This idea may also hold true for TEC regeneration after depletive regimens. Additive restoration of TECs by 4 weeks after BMT observed in KGF ϩ PFT-␤-treated BM transplant recipients may be due to PFT-␤-mediated protection combined with TEC expansion driven by mature SP thymocytederived crosstalk.…”

Section: Discussionmentioning

confidence: 99%

Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation

Kelly

Goren

Taylor

et al. 2010

Blood

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Myeloablative conditioning before bone marrow transplantation (BMT) results in thymic epithelial cell (TEC) injury, T-cell immune deficiency, and susceptibility to opportunistic infections. Conditioning regimen-induced TEC damage directly contributes to slow thymopoietic recovery after BMT. Keratinocyte growth factor (KGF) is a TEC mitogen that stimulates proliferation and, when given before conditioning, reduces TEC injury. Some TEC subsets are refractory to KGF and functional T-cell responses are not fully restored in KGF-treated BM transplant recipients. Therefore, we investigated whether the addition of a pharmacologic inhibitor, PFT-␤, to transiently inhibit p53 during radiotherapy could spare TECs from radiation-induced damage in congenic and allogeneic BMTs. IntroductionAllogeneic bone marrow transplantation (BMT) is used to treat malignant and nonmalignant disorders. 1,2 Chemoradiotherapy conditioning preceding donor graft infusion damages thymic stroma, severely delaying peripheral CD4 ϩ and CD8 ϩ T-cell reconstitution. [2][3][4][5][6] Thus, BM transplant recipients are at increased risk of opportunistic fungal and viral infections. 7 Thymic stroma is composed of a 3-dimensional matrix of thymic epithelial cells (TECs), fibroblasts, macrophages, dendritic cells (DCs), and mesenchymal cells. 8 Critical signals are supplied by TECs to developing thymocytes directing their thymic ingress, 9,10 survival, 11,12 trafficking, 11 selection, 13 and export. 11 Conditioning depletes TECs, impairing T-cell production for prolonged periods of time after BMT. [14][15][16][17] Restoring thymic function would speed peripheral T-cell recovery after BMT.Developing thymocytes can be distinguished by their CD4 and CD8 cell surface expression. CD4 Ϫ CD8 Ϫ (double-negative, DN) thymocytes mature to become CD4 ϩ CD8 ϩ (double-positive, DP) thymocytes and undergo positive selection on cortical TECs (cTECs). DP thymocytes continue their maturation into CD4 ϩ or CD8 ϩ (single-positive, SP) thymocytes and migrate into the thymic medulla where negative selection is mediated by medullary TECs (mTECs) and medullary DCs. 8 SP thymocytes complete their maturation in the medulla and are exported into the periphery as mature T cells. 13 Keratinocyte growth factor (KGF) is a fibroblast growth factor family member that controls cell migration, proliferation, and differentiation in epithelial tissues. 18 Endogenous KGF is upregulated in mucosal tissues after injury, and exogenous KGF enhances protection/repair of epithelial cells in models of chemoradiotherapy-induced injury. 18 KGF is approved by the Food and Drug Administration for prevention of oral mucositis associated with high-dose chemoradiotherapy and hematopoietic stem cell transplantation. [19][20][21] KGF is produced by thymic mesenchymal cells and binds exclusively to FGFR2-IIIb expressed by TECs. 15,22 KGF is a potent mitogen for TECs. 23 KGF pretreatment prevents thymic injury and prolonged T-cell deficiency in murine BMT models. 15,[23][24][25][26][27] KGF facilitates alloe...

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“…1C). The association of the expression of DLL4, specifically to the DN microenvironment, has been reported (31)(32)(33), in that the different levels of expression of Ly51 seem to distinguish between two functionally different cTEC subsets. Mutant mice showed alterations in Ly51 expression and the distribution of these cTEC subpopulations.…”

Section: Ephrin-b Expression On Both Tecs and Thymocytes Is Necessarymentioning

confidence: 99%

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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Cutting Edge: Thymic Crosstalk Regulates Delta-Like 4 Expression on Cortical Epithelial Cells

Cited by 65 publications

References 22 publications

Thymocyte Selection Regulates the Homeostasis of IL-7–Expressing Thymic Cortical Epithelial Cells In Vivo

Thymocyte Selection Regulates the Homeostasis of IL-7–Expressing Thymic Cortical Epithelial Cells In Vivo

Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation

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

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