Divergent molecular events underlying initial T-cell commitment in human prenatal and postnatal thymus

Area of Science:

• Immunology
• Developmental Biology
• Genomics

Background:

• T-cell development in the thymus is a complex process involving dynamic gene expression changes.
• Recent single-cell studies have characterized human T-cell development, but prenatal-postnatal differences remain unclear.
• Transcriptional heterogeneity and posttranscriptional regulation, like alternative polyadenylation, are largely unknown in developing human thymocytes.

Purpose of the Study:

• To investigate the differences in T-cell development between human prenatal and postnatal thymus.
• To characterize transcriptional heterogeneity and alternative polyadenylation dynamics during T-cell development.
• To provide a comprehensive resource for understanding human T lymphopoiesis.

Main Methods:

• Integrative single-cell analyses of thymocytes at distinct developmental stages.
• Comprehensive comparison of prenatal and postnatal CD4-CD8- double-negative (DN) cells.
• Quantification of transcriptome-wide alternative polyadenylation changes.

Main Results:

• Prenatal DN subpopulations show distinct biological processes and activated metabolic programs.
• Significant differences in gene expression dynamics for cell cycle, metabolism, signaling, homing, and commitment genes between prenatal and postnatal thymocytes.
• Diverse preferences in alternative polyadenylation site usage across T-cell development trajectories.

Conclusions:

• Human T-cell development exhibits significant transcriptional heterogeneity and dynamic alternative polyadenylation.
• These findings highlight key differences in early T-cell development between prenatal and postnatal stages.
• The study provides a valuable resource for understanding human T lymphopoiesis.