Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow.
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.
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.
Vionnie W C
VW
Yu
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.
Borja
B
Saez
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.
Colleen
C
Cook
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.
Sutada
S
Lotinun
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.
Ana
A
Pardo-Saganta
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.
Ying-Hua
YH
Wang
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.
Stefania
S
Lymperi
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.
Francesca
F
Ferraro
Department of Hematology and Erasmus Stem Cell Institute, Erasmus University Medical Center Cancer Institute, 3015 CE Rotterdam, Netherlands.
Marc H G P
MH
Raaijmakers
Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215.
Joy Y
JY
Wu
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
Lan
L
Zhou
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.
Jayaraj
J
Rajagopal
Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02215.
Henry M
HM
Kronenberg
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.
Roland
R
Baron
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 david_scadden@harvard.edu.
David T
DT
Scadden
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology*; D002135:Calcium-Binding Proteins; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D015675:Osteocalcin / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015675:Osteocalcin