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

Yu VW, Saez B, Cook C, Lotinun S, Pardo-Saganta A, Wang YH, Lymperi S, Ferraro F, Raaijmakers MH, Wu JY, Zhou L, Rajagopal J, Kronenberg HM, Baron R, Scadden DT - J. Exp. Med. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

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Conditional deletion of DLL4 or Notch ligands in Ocn+ cells impaired T lymphopoiesis. (A) OcnCreER+/−;Dll4Fl/Fl mutants and OcnCreER+/−;Dll4+/+ control littermates were injected with 2mg 4-OH-tamoxifen/15 g BW eight times over 4 wk to induce deletion of the DLL4 ligand. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed 3 times independently; n = 9–10 mice/group. Data show mean ± SEM. (B) OcnCreER+/−;Mib1Fl/Fl mutants and OcnCreER+/−;Mib1+/+ control littermates were injected with 2 mg 4-OH-tamoxifen/15 g BW 8 times over 4 wk to induce deletion of the Mib1 gene. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed twice independently; n = 6–8 mice/group. Data show mean ± SEM.
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fig6: Conditional deletion of DLL4 or Notch ligands in Ocn+ cells impaired T lymphopoiesis. (A) OcnCreER+/−;Dll4Fl/Fl mutants and OcnCreER+/−;Dll4+/+ control littermates were injected with 2mg 4-OH-tamoxifen/15 g BW eight times over 4 wk to induce deletion of the DLL4 ligand. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed 3 times independently; n = 9–10 mice/group. Data show mean ± SEM. (B) OcnCreER+/−;Mib1Fl/Fl mutants and OcnCreER+/−;Mib1+/+ control littermates were injected with 2 mg 4-OH-tamoxifen/15 g BW 8 times over 4 wk to induce deletion of the Mib1 gene. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed twice independently; n = 6–8 mice/group. Data show mean ± SEM.

Mentions: We tested whether Notch ligand expression specifically by Ocn+ cells caused the lymphopoietic phenotype using the conditional OcnCreER;DLL4Fl/Fl strain. Ocn+ cell-specific DLL4 deletion resulted in significantly reduced Notch-activated CLP, T cell–competent Ly6D−-CLP, and CCR7-expressing Ly6D−-CLP (Fig. 6 A, discussed in the following paragraphs), with a decrease comparable in magnitude to that seen with Ocn+ cell depletion (Fig. 2 B). Thymic intermediates and blood T-lymphocytes were also decreased (Fig. 6 A).


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

Yu VW, Saez B, Cook C, Lotinun S, Pardo-Saganta A, Wang YH, Lymperi S, Ferraro F, Raaijmakers MH, Wu JY, Zhou L, Rajagopal J, Kronenberg HM, Baron R, Scadden DT - J. Exp. Med. (2015)

Conditional deletion of DLL4 or Notch ligands in Ocn+ cells impaired T lymphopoiesis. (A) OcnCreER+/−;Dll4Fl/Fl mutants and OcnCreER+/−;Dll4+/+ control littermates were injected with 2mg 4-OH-tamoxifen/15 g BW eight times over 4 wk to induce deletion of the DLL4 ligand. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed 3 times independently; n = 9–10 mice/group. Data show mean ± SEM. (B) OcnCreER+/−;Mib1Fl/Fl mutants and OcnCreER+/−;Mib1+/+ control littermates were injected with 2 mg 4-OH-tamoxifen/15 g BW 8 times over 4 wk to induce deletion of the Mib1 gene. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed twice independently; n = 6–8 mice/group. Data show mean ± SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4419348&req=5

fig6: Conditional deletion of DLL4 or Notch ligands in Ocn+ cells impaired T lymphopoiesis. (A) OcnCreER+/−;Dll4Fl/Fl mutants and OcnCreER+/−;Dll4+/+ control littermates were injected with 2mg 4-OH-tamoxifen/15 g BW eight times over 4 wk to induce deletion of the DLL4 ligand. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed 3 times independently; n = 9–10 mice/group. Data show mean ± SEM. (B) OcnCreER+/−;Mib1Fl/Fl mutants and OcnCreER+/−;Mib1+/+ control littermates were injected with 2 mg 4-OH-tamoxifen/15 g BW 8 times over 4 wk to induce deletion of the Mib1 gene. Mice were harvested immediately after 4 wk of deletion and bone marrow CLPs, thymic T cell progenitors, and peripheral blood mature T cells were enumerated by flow cytometry. Experiment was performed twice independently; n = 6–8 mice/group. Data show mean ± SEM.
Mentions: We tested whether Notch ligand expression specifically by Ocn+ cells caused the lymphopoietic phenotype using the conditional OcnCreER;DLL4Fl/Fl strain. Ocn+ cell-specific DLL4 deletion resulted in significantly reduced Notch-activated CLP, T cell–competent Ly6D−-CLP, and CCR7-expressing Ly6D−-CLP (Fig. 6 A, discussed in the following paragraphs), with a decrease comparable in magnitude to that seen with Ocn+ cell depletion (Fig. 2 B). Thymic intermediates and blood T-lymphocytes were also decreased (Fig. 6 A).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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.

Show MeSH
Related in: MedlinePlus