Allele-specific expression changes dynamically during T cell activation in HLA and other autoimmune loci

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Autoimmune susceptibility variants are frequently found in regulatory elements of memory CD4+ T cells.
• Understanding how genetic variations impact gene expression in T cells is crucial for elucidating autoimmunity mechanisms.

Purpose of the Study:

• To investigate the dynamic changes in genetic regulatory effects during memory CD4+ T cell activation.
• To determine how these dynamics relate to autoimmune susceptibility loci.

Main Methods:

• High-depth RNA sequencing was performed on memory CD4+ T cells from healthy individuals across eight time points post-activation.
• CRISPR-Cas9 genomic editing was employed to validate the functional impact of specific variants.

Main Results:

• Widespread, dynamic allele-specific expression was observed, with allele balance shifting over time.
• Genes within autoimmune loci showed a fourfold enrichment for these dynamic regulatory effects.
• Dynamic regulatory effects were identified within six HLA genes, including distinct transcriptional programs for HLA-DQB1 alleles.
• A promoter variant was confirmed as causal for T cell-specific HLA-DQB1 expression control.

Conclusions:

• Genetic variations in cis-regulatory elements modulate gene expression dynamically based on lymphocyte activation status.
• These findings contribute to understanding the complexity of immune responses and the genetic basis of autoimmunity.