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

Area of Science:

• Immunology
• Developmental Biology
• Skeletal Biology

Background:

• The origin and regulation of T cell progenitors in the bone marrow remain incompletely understood.
• Molecular drivers controlling the generation of thymus-seeding progenitors are largely undefined.

Purpose of the Study:

• To investigate the role of osteocalcin (Ocn)-expressing cells in the bone marrow on T cell progenitor generation.
• To identify molecular signals from bone marrow mesenchymal cells that influence thymopoiesis.

Main Methods:

• In vivo genetic deletion of osteocalcin (Ocn)-expressing cells.
• Analysis of hematopoietic stem and progenitor cells in bone marrow and thymus.
• Selective depletion of DLL4 ligand from Ocn-expressing cells.
• Assessment of T cell development and thymic function.

Main Results:

• Specific deletion of Ocn(+) cells significantly reduced T-competent progenitors and thymus-homing receptor expression in bone marrow.
• Intrathymic T cell precursors and mature T cell generation were decreased despite normal thymic function.
• Selective depletion of DLL4 from Ocn(+) cells mimicked the observed reduction in T cell progenitor generation.

Conclusions:

• Mesenchymal osteocalcin (Ocn)-expressing cells in the bone marrow are essential for generating thymus-seeding progenitors.
• The Notch ligand DLL4, expressed by Ocn(+) cells, is a key molecular driver for this process.
• These findings establish a direct link between skeletal biology and the regulation of adaptive T cell immunity.