Abstract
Genome-wide association studies (GWAS) in immune-mediated diseases have identified over 150 associated genomic loci. Many of these loci play a role in T cell responses, and regulation of T cell differentiation plays a critical role in immune-mediated diseases; however, the relationship between implicated disease loci and T cell differentiation is incompletely understood. To further address this relationship, we examined differential gene expression in naïve human CD4+ T cells, as well as in in vitro differentiated Th1, memory Th17-negative and Th17-enriched CD4+ T cells subsets using microarray and RNASeq. We observed a marked enrichment for increased expression in memory CD4+ compared to naïve CD4+ T cells of genes contained among immune–mediated disease loci. Within memory T cells, expression of disease-associated genes was typically increased in Th17-enriched compared to Th17-negative cells. Utilizing RNASeq and promoter methylation studies, we identified a differential regulation pattern for genes solely expressed in Th17 cells (IL17A and CCL20) compared to genes expressed in both Th17 and Th1 cells (IL23R and IL12RB2), where high levels of promoter methylation are correlated to near zero RNASeq levels for IL17A and CCL20. These findings have implications for human Th17 celI plasticity and for the regulation of Th17-Th1 expression signatures. Importantly, utilizing RNASeq we found an abundant isoform of IL23R terminating before the transmembrane domain that was enriched in Th17 cells. In addition to molecular resolution, we find that RNASeq provides significantly improved power to define differential gene expression and identify alternative gene variants relative to microarray analysis. The comprehensive integration of differential gene expression between cell subsets with disease-association signals, and functional pathways provides insight into disease pathogenesis.
Highlights
Genome-wide association studies in immune-mediated diseases have implicated a variety of inflammatory pathways, with a striking overlap of major association signals across disease subtypes [1]
Th17 cells arise from a CD161+CD4+ T cell precursor [10,11,12] and CCR6 plays a key role in Th17 cell trafficking to the intestine [13,14]
Comparable fractions of expanded CD161CCR6- and CD161+CCR6+ cells express IFNc; as expected, these fractions are lower than those attained by expansion of naıve CD4+ T cells under Th1-skewing conditions (Figure 1B)
Summary
Genome-wide association studies in immune-mediated diseases have implicated a variety of inflammatory pathways, with a striking overlap of major association signals across disease subtypes [1]. One of the most significant is the interleukin 23 (IL-23) pathway, highlighted by associations within the IL23R (interleukin 23 receptor, alpha chain) gene region to inflammatory bowel disease (IBD) [2], psoriasis [3], and ankylosing spondylitis [4]. The traditional view of an initiating role of IFNc, IL-12 and Th1 cells in immune-mediated human and disease models of autoimmunity has been revised both by human genetic association studies implicating the IL-23 pathway, as well as the requirement for IL23, and not the IL-12 pathway, in mouse models of intestinal, dermatologic and central nervous system inflammation [16,17,18,19]
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