Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow

VWC Yu, B Saez, C Cook, S Lotinun, A Pardo-Saganta, YH Wang, S Lymperi, F Ferraro, Marc Raaijmakers, JY Wu, L Zhou, J Rajagopal, HM Kronenberg, R Baron, DT Scadden

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Abstract

Production of the cells that ultimately populate the thymus to generate alpha/beta T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function. The Notch ligand DLL4 is abundantly expressed on bone marrow Ocn(+) cells, and selective depletion of DLL4 from these cells recapitulated the thymopoietic abnormality. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell-based adaptive immunity.
Original languageUndefined/Unknown
Pages (from-to)759-774
Number of pages16
JournalJournal of Experimental Medicine
Volume212
Issue number5
DOIs
Publication statusPublished - 2015

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