Strain-specific variation drives CD8+ T cell activation responses 2305504

Abstract

Abstract Introduction In the rapidly evolving immune system, genetic variation between individuals is a major driver of differential responses to infection. Previous studies in human and mouse have linked gene expression changes within immune cells to variable immune response between individuals. However, the regulatory impacts of genetic variation on genes driving immune cell activation are not well understood. Here, we used eight recombinant inbred mice strains (which capture nearly 90% of the genetic variation across the mouse genome) and the Diversity Outbred (DO) mice as models of genetic variation to study strain-specific differences in the activation of CD8+ T cells. By activating CD8+ T cells through both TCR stimulation and bystander activation, we intend to characterize the genes driving differences in immune activation. Methods Using CD8+ T cells from the eight mice strains that underlie the DO mice, we 1) generated single-cell RNA-seq data from control, TCR stimulation, and bystander activation culture conditions, and 2) characterized proliferation and activation phenotypes before and after TCR stimulation and bystander activation. We also performed GWAS analyses on 90 DO mice using measures of activation and cell surface protein expression in CD8+ T cells to further link genotypes to activation phenotypes. Results We identified hundreds of differentially expressed genes across both TCR stimulation and bystander activation that also varied by strain in CD8+ T cells. Transcription factors with key roles in CD8+ T cell activation such as AP-1 family members Jun and Jund were differentially expressed across strains, alongside receptors such as Il7r and Il18r1. Our preliminary GWAS analyses on DO mice corroborated strain-specific expression of Il18r1 and provided further loci for investigation. Conclusion For the first time, we have identified hundreds of genes that differ across activation and strain underlying TCR stimulation and bystander activation in CD8+ T cells across eight mice strains. Funding Source F31AI183775 (NIAID F31 to Jason Chobirko); R01AI110613 (NIAID R01 to Andrew Grimson); U24AI152176 (NIAID U24 to Andrew Grimson) Topic Categories Computational and Systems Immunology (COMP)