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Cutting Edge: Thymic Crosstalk Regulates Delta-Like 4 Expression on Cortical Epithelial Cells¹

Emma Fiorini^*, Isabel Ferrero^*, Estelle Merck^*, Stéphanie Favre, Michel Pierres, Sanjiv A. Luther and H. Robson MacDonald^2,*

^* Ludwig Institute for Cancer Research, Lausanne Branch, and Institute for Biochemistry, University of Lausanne, Epalinges, Switzerland; and Centre d’Immunologie de Marseille-Luminy, Marseille, France

Interactions between Notch1 receptors on lymphoid progenitors and Delta-like 4 (DL4) ligands on cortical thymic epithelial cells (cTEC) are essential for T cell lineage commitment, expansion, and maturation in the thymus. Using a novel mAb against DL4, we show that DL4 levels on cTEC are very high in the fetal and neonatal thymus when thymocyte expansion is maximal but decrease dramatically in the adult when steady-state homeostasis is attained. Analysis of mutant mouse strains where thymocyte development is blocked at different stages indicates that lymphostromal interactions ("thymus crosstalk") are required for DL4 down-regulation on cTEC. Reconstitution of thymocyte development in these mutant mice further suggests that maturation of thymocytes to the CD4⁺CD8⁺ stage and concomitant expansion are needed to promote DL4 down-regulation on cTEC. Collectively, our data support a model where thymic crosstalk quantitatively regulates the rate of Notch1-dependent thymopoiesis by controlling DL4 expression levels on cTEC.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Marie Heim-Vögtlin Fellowship PMP DB-115611/1 (to E.F.), FP6 Marie Curie Fellowship EIF023521 (to E.M.), and Swiss National Science Foundation Professor Grant PP00A-116896 (to S.A.L.).

² Address correspondence and reprint requests to Dr. H. Robson MacDonald, Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CH-1066 Epalinges, Switzerland. E-mail address: hughrobson.macdonald{at}licr.unil.ch

³ Abbreviations used in this paper: DN, double negative (CD4^–CD8^–); DN1, CD44⁺CD25^–; DN2, CD44⁺CD25⁺; DN3, CD44^–CD25⁺; DN4, CD44^–CD25^–; BM, bone marrow; DL, Delta-like; DP, double positive (CD4⁺CD8⁺); E15, embryonic day 15; N1, Notch1; PanCK, pancytokeratin; TEC, thymic epithelial cell; cTEC, cortical TEC; mTEC, medullary TEC; WT, wild type.

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