ZFP36L1 and ZFP36L2 cooperatively regulate thymic epithelial cell function to prevent early-onset thymic involution

Area of Science:

• Immunology
• Developmental Biology
• Molecular Biology

Background:

• The thymus is essential for T-cell maturation, but its function declines with age.
• Thymic epithelial cells (TECs) are critical for T-cell development, with distinct cortical (c) and medullary (m) subsets.
• The molecular regulation of TEC differentiation from progenitors is not fully understood.

Purpose of the Study:

• To investigate the role of RNA-binding proteins ZFP36L1 and ZFP36L2 in TEC differentiation and thymic function.
• To elucidate the molecular mechanisms by which ZFP36L1 and ZFP36L2 regulate the TEC microenvironment.

Main Methods:

• Utilized dual conditional knockout (dcKO) and lineage-tracing mouse models.
• Performed single-cell transcriptomics to analyze TEC populations and transcriptional programs.
• Conducted fate-mapping analysis to trace TEC progenitor differentiation.

Main Results:

• TEC-specific deletion of Zfp36l1 and Zfp36l2 caused early thymic hypoplasia and reduced TEC and thymocyte numbers.
• Single-cell transcriptomics revealed altered TEC subset composition and metabolic gene dysregulation.
• Fate-mapping showed disrupted differentiation trajectories from TEC progenitors to mature TECs.

Conclusions:

• ZFP36L1 and ZFP36L2 cooperatively maintain TEC differentiation and thymic function.
• Their deficiency impairs TEC development, leading to premature thymic involution.
• These findings highlight a critical role for post-transcriptional regulation in sustaining thymic immunity.