Psoriasis risk allele function in activated Th1/17 cells with "memory" to antigen exposure

Abstract

Most causal variants for complex diseases are expected to affect gene regulation in a cell- and context-specific manner. Hence, identification of such dynamically functioning variants requires functional readouts in disease-relevant tissues and context. In this study, we prioritized causal variants for psoriasis by enhancing functional annotations from disease-relevant cells. We demonstrate that disease-relevant immune cells, unlike most body tissues, possess functional annotations matching candidate causal SNPs. Specifically, we identified an eQTL rs4672505 affecting B3GNT2 gene expression only in Th1/Th17 cells with a memory phenotype, i.e., antigen-experienced cells. This eQTL also matched an enhancer chromatin mark exclusive to memory T cells and absent in other tissues. For this eQTL rs4672505, the risk allele A reduces B3GNT2 gene expression. B3GNT2 deficiency in murine models reduces the glycosylation of the CD28 co-receptor and increases T cell activation upon antigen stimulation. Notably, memory T cells also require CD28 co-stimulation, which occurs only when antigen-presenting cells encounter an infection. Thus, our findings suggest that the risk allele likely increases co- stimulation of memory Th1/Th17 cells by their cognate antigens under infection. This putative mechanism aligns with the observation that psoriasis can manifest, exacerbate, and recur after infection.