HUMAN NAÏVE CD8+ T CELLS EXHIBIT DISTINCT AGE-RELATED GENE REGULATORY PROGRAMS
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The immune system plays an essential role in protecting hosts against pathogens and diseases. CD8+ T cells are a major component of the adaptive immune system, recognizing and killing cancerous and infected cells. Neonatal CD8+ T cells form a distinct subset of lymphocytes, compared to their more conventional adult counterparts. Neonatal CD8+ T cells respond to infections more quickly but form fewer memory cells, making them well-suited for the dynamic early-life environment. Recent studies have revealed differences in the transcriptome of neonatal naïve CD8+ T cells compared to adults, but the underlying regulatory mechanisms remain unclear. We are investigating gene regulatory pathways in human CD8+ T cells, focusing on key regulators that govern the contrasting properties of adult and neonatal naïve CD8+ T cells. To explore these mechanisms, we used RNA-seq and PRO-seq in human CD8+ T cells. RNA-seq profiles steady-state mRNA, while PRO-seq captures nascent RNA, allowing differentiation and quantification of transcriptional regulation. PRO-seq also identifies enhancer RNAs, which are optimal markers for identification of active enhancers genome wide. Our integrative analysis of PRO-seq and RNA-seq revealed age-specific regulation of immune-related genes. By linking cis-regulatory elements identified by PRO-seq to target genes, we identified transcription factors likely involved in age-related transcriptional regulation in human naïve CD8+ cells. Notably, IRF4, a transcription factor required for T cell effector functions, is upregulated in neonatal naïve CD8+ cells. To further explore the role of IRF4, we used CUT&Tag to examine binding of IRF4 across the genome, revealing cooperation between IRF4 and AP-1 TF families in neonatal naïve CD8+ T cells. In conclusion, this study provides a comprehensive profile of immune-related genes subject to age-specific regulation, offering valuable insights into early-life immunology.