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

Vionnie W.C. Yu, Borja Saez, Colleen Cook, Sutada Lotinun, Ana Pardo-Saganta, Ying Hua Wang, Stefania Lymperi, Francesca Ferraro, Marc H.G.P. Raaijmakers, Joy Y. Wu, Lan Zhou, Jayaraj Rajagopal, Henry M. Kronenberg, Roland Baron, D. T. Scadden

Research output: Contribution to journalArticlepeer-review

91 Scopus citations

Abstract

Production of the cells that ultimately populate the thymus to generate α/β 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 languageEnglish
Pages (from-to)759-774
Number of pages16
JournalJournal of Experimental Medicine
Volume212
Issue number5
DOIs
StatePublished - May 4 2015

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