Indispensable epigenetic control of thymic epithelial cell development and function by polycomb repressive complex 2.

Area of Science:

• Immunology
• Epigenetics
• Developmental Biology

Background:

• Thymic T cell development relies on thymic epithelial cells (TECs) for molecular cues.
• The epigenetic landscape, particularly H3K27me3 marks catalyzed by Polycomb repressive complex 2 (PRC2), regulates TECs.
• Dysregulation of TECs impacts T cell repertoire selection.

Purpose of the Study:

• To investigate the role of PRC2 in TEC differentiation and function.
• To determine the consequences of PRC2 deficiency on thymus development and T cell repertoire.
• To elucidate the epigenetic mechanisms governing TEC lineage commitment.

Main Methods:

• Generation of a TEC-specific PRC2 deficiency mouse model.
• Analysis of thymus histology and cellularity.
• Transcriptomic profiling of TEC populations.
• Assessment of T cell receptor (TCR) repertoire diversity.

Main Results:

• TEC-specific PRC2 deficiency leads to a hypoplastic thymus.
• Reduced antigen presentation and impaired T cell repertoire selection were observed.
• A distinct medullary TEC lineage emerged in the absence of PRC2, but incompletely compensated for TEC loss.
• Cortical TEC numbers remained unchanged, while medullary TECs were reduced.
• Absence of PRC2 resulted in decreased TCR diversity.

Conclusions:

• Normal PRC2 activity and H3K27me3 deposition are essential for proper TEC lineage differentiation and function.
• PRC2 deficiency disrupts the thymic scaffold, leading to impaired T cell development and repertoire formation.
• The thymus cannot fully compensate for the loss of canonical TECs due to PRC2 absence.