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; David T Scadden

doi:10.1084/jem.20141843

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

J Exp Med. 2015 May 4;212(5):759-74. doi: 10.1084/jem.20141843. Epub 2015 Apr 27.

Authors

Affiliations

¹ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02215 Harvard Stem Cell Institute, Cambridge, MA 02215 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02215.
² Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02215 Department of Physiology and STAR on Craniofacial and Skeletal Disorders, Chulalongkorn University, Bangkok 10330, Thailand.
³ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02215 Harvard Stem Cell Institute, Cambridge, MA 02215 Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA 02215.
⁴ Department of Hematology and Erasmus Stem Cell Institute, Erasmus University Medical Center Cancer Institute, 3015 CE Rotterdam, Netherlands.
⁵ Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215.
⁶ Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
⁷ Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA 02215 Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215.
⁸ Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02215 Harvard Stem Cell Institute, Cambridge, MA 02215 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02215 [email protected].

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing
Animals
Bone Marrow Cells / cytology
Bone Marrow Cells / immunology*
Calcium-Binding Proteins
Gene Expression Regulation / genetics
Gene Expression Regulation / immunology
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / immunology*
Membrane Proteins / genetics
Membrane Proteins / immunology*
Mesenchymal Stem Cells / cytology
Mesenchymal Stem Cells / immunology*
Mice
Mice, Transgenic
Osteocalcin / genetics
Osteocalcin / immunology
Receptors, Antigen, T-Cell, alpha-beta / immunology
T-Lymphocytes / immunology*
Thymus Gland / cytology
Thymus Gland / immunology*

Substances

Adaptor Proteins, Signal Transducing
Calcium-Binding Proteins
DLL4 protein, mouse
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Receptors, Antigen, T-Cell, alpha-beta
Osteocalcin

Abstract

Publication types

MeSH terms

Substances

Grants and funding