Impact of the Multiple Sclerosis associated genetic variant CD226 Gly307Ser on human CD8 T cell functions

Background and Objectives: The rs763361 non-synonymous (Gly307Ser) variant in the CD226 gene has been identified as a risk factor for several immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may be one of the genetic driving forces contributing to suceptibility to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the pro-inflammatory potential of CD4 T cells. However, the impact of this CD gene variant on CD8 T cell functions, a population that also plays a key role in MS, remain T to be determined. Methods: In order to study whether the CD226 risk variant affects human CD8 T cells functions, we used CD8 T cells isolated from PBMC of 16-age matched healthy donors homozygous for either the protective or risk allele of CD226. We characterized these CD8 T cells upon TCR stimulation using high-parametric flow cytometry, bulk RNAseq, and through characterization of canonical signaling pathways and cytokine production. Results: Upon TCR engagment, the phenotype of ex vivo CD8 T cells bearing the protective (CD226-307Gly) or the risk (CD226-307Ser) allele of CD226 was largely overlapping. However, transcriptomic signature of CD8 T cells from the donor carrying the risk allele presented an enrichment in TCR, JAK/STAT and INFg signaling.