Global transcriptome analysis of T-competent progenitors in the bone marrow

Area of Science:

• Immunology
• Developmental Biology
• Skeletal Biology

Background:

• T cell development typically occurs in the thymus.
• Molecular mechanisms linking bone marrow progenitor cells to thymus-seeding T cell precursors are not fully understood.

Purpose of the Study:

• To investigate the role of osteocalcin (Ocn)-expressing bone cells in regulating T cell progenitor development in the bone marrow.
• To identify molecular drivers produced by bone cells that influence T cell precursor generation and thymic seeding.

Main Methods:

• Utilized an inducible diphtheria toxin receptor system (OcnCre;iDTR) for selective depletion of osteocalcin-expressing cells in mice.
• Analyzed the impact of Ocn-expressing cell depletion on T-competent common lymphoid progenitors (Ly6D(-) CLPs) in the bone marrow and T cell populations in the thymus.
• Performed transcriptome profiling of Ly6D(-) CLPs from Ocn-deleted and control mice.

Main Results:

• Depletion of osteocalcin-expressing cells reduced Ly6D(-) CLPs in the bone marrow and led to a loss of T cells in the thymus.
• Osteocalcin-expressing cells were found to express DLL4, a Notch ligand crucial for Ly6D(-) CLP production.
• These bone cells also express CCR7 and PSGL1, molecules involved in guiding progenitor cells to the thymus.

Conclusions:

• Mesenchymal cells in the bone marrow expressing osteocalcin are critical regulators of thymus-seeding progenitor generation.
• This study establishes a direct link between skeletal biology and the production of T cell-based adaptive immunity.
• The findings provide new insights into the molecular control of early T cell development.