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Mature Human Thymocytes Migrate on Laminin-5 with Activation of Metalloproteinase-14 and Cleavage of CD44¹

Mylène Vivinus-Nebot^*,, Patricia Rousselle, Jean-Philippe Breittmayer^*, Claire Cenciarini^*, Sonia Berrih-Aknin, Suzanne Spong^¶, Pasi Nokelainen^¶, Françoise Cottrez^*, M. Peter Marinkovich^|| and Alain Bernard^2,*,

^* Institut National de la Santé et de la Recherche Médicale, Unité 576, Nice, France; Laboratoire d’Immunologie, Centre Hospitalier Universitaire, Nice, France; IBCP, Unité Mixte de Recherche 5086, Lyon, France; Centre National de la Recherche Scientifique, Le Plessis Robinson, France; ^¶ FibroGen, South San Francisco, CA 94080; and ^|| Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305

We have previously shown that laminin-5 is expressed in the human thymic medulla, in which mature thymocytes are located. We now report that laminin-5 promotes migration of mature medullary thymocytes, whereas it has no effect on cortical immature thymocytes. Migration was inhibited by blocking mAbs directed against laminin-5 integrin receptors and by inhibitors of metalloproteinases. Interactions of thymocytes with laminin-5 induced a strong up-regulation of active metalloproteinase-14. However, we found that thymocytes did not cleave the laminin-5 ₂ chain, suggesting that they do not use the same pathway as epithelial cells to migrate on laminin-5. Interactions of thymocytes with laminin-5 also induced the release of a soluble fragment of CD44 cell surface molecule. Moreover, CD44-rich supernatants induced thymocyte migration in contrast with supernatants depleted in CD44 by immunoadsorption. CD44 cleavage was recently reported to be due to metalloproteinase-14 activation and led to increased migration in cancer cells. Thus, in this study, we show that laminin-5 promotes human mature thymocyte migration in vitro via a multimolecular mechanism involving laminin-5 integrin receptors, metalloproteinase-14 and CD44. These data suggest that, in vivo, laminin-5 may function in the migration of mature thymocytes within the medulla and be part of the thymic emigration process.

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