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Title: Pathogenic implications for autoimmune mechanisms derived by comparative eQTL analysis of CD4+ versus CD8+ T cells}
Article:
Abstract:
Inappropriate activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune and inflammatory diseases. Studies on disease-associated genetic polymorphisms have highlighted the importance of biological context for many regulatory variants, which is particularly relevant in understanding the genetic regulation of the immune system and its cellular phenotypes. Here we show cell type-specific regulation of transcript levels of genes associated with several autoimmune diseases in CD4+ and CD8+ T cells including a trans-acting regulatory locus at chr12q13. 2 containing the rs1131017 SNP in the RPS26 gene. Most remarkably, we identify a common missense variant in IL27, associated with type 1 diabetes that results in decreased functional activity of the protein and reduced expression levels of downstream IRF1 and STAT1 in CD4+ T cells only. Altogether, our results indicate that eQTL mapping in purified T cells provides novel functional insights into polymorphisms and pathways associated with autoimmune diseases.
Introduction:
T cells are essential elements of the adaptive immune response[1]. CD4+ T cells, together with an appropriate cytokine environment, are required for the activation and differentiation of CD8+ T cells that mediate defense and pathogen clearance during various infections[2]. The role of CD4+ T cells is also necessary for B cells and macrophages to execute their protective functions. T cells are activated and start to differentiate in response to complex stimuli involving cytokines, membrane receptors and transcription factors. Signaling through T cell receptor and costimulatory molecules induces their rapid proliferation and clonal expansion, and differentiation into effector and memory T cell subtypes[3]. Faulty activation or inadequate regulation of CD4+ and CD8+ T cells may contribute to the initiation and progression of multiple autoimmune diseases, including type 1 diabetes( T1D), rheumatoid arthritis( RA), autoimmune thyroiditis, systemic lupus erythematosus( SLE), multiple sclerosis, psoriasis, inflammatory bowel disease, as well as allergy and asthma[4, 5]. In addition, a distinct lineage of CD4+ T cells, regulatory T cells, have a central role in the control of the pathogenesis of autoimmune and inflammatory diseases[6]. Genome-wide association studies( GWAS) have identified thousands of single nucleotide polymorphisms( SNPs) associated with various immune related diseases[7–12]. Studies of the consequences of the risk alleles in biologically relevant contexts for different diseases have stressed the importance of the tissue and cell type-specificity of the regulatory variants[13–15]. We have recently shown that by mapping eQTLs in a sufficiently large sample set, it is possible to identify cell type-specific effects in whole blood, but the challenge to distinguish the cells responsible for the associations remains[16, 17]. The power of studying expression-associated genetic variants in purified cells types has now been illustrated for B cells, monocytes, neutrophils, T regulatory cells and CD4+ T cells[18–21], which allowed the identification of functional roles for several polymorphisms at autoimmune and even neurodegenerative disease loci. Meanwhile, some particularly interesting cis- and trans-eQTLs identified in whole blood could not be attributed to these cell types, and require an expanded survey of cells involved in immune response. To this end, we purified CD4+ and CD8+ T cells from the peripheral blood of 313 healthy individuals for genome-wide mapping of genetic variation affecting the expression of genes involved in immune response. Our analysis characterizes both the extent of genetic control of gene expression in T cells and its cellular specificity, as well as variation in isoform levels of genes and their association with epigenetic changes. We show that integrating knowledge from GWAS with eQTLs enables us to clarify the functional consequences of disease-associated variants and assess the enrichment of autoimmune response. Finally, we highlight a common T1D-associated missense variant in IL27 affecting the STAT1 and IRF1 pathway in CD4+ T cells. Our analysis provides insights into the basic processes of the regulation of gene expression in T cells and advances our understanding about the pathways involved with disease susceptibility in the adaptive immune system.
Discussion:
We here report eQTL mapping in purified CD4+ and CD8+ T cells and reveal multiple effects on regulation of genes associated with autoimmune diseases. The eQTL studies in cell subtypes have both demonstrated a high level of specificity as their effects vary across cell types, as well as remarkable sensitivity despite their several fold smaller sample sizes[24, 25]. Indeed, we also observed many cis-eQTLs identified in CD4+ and CD8+ T cells that were shared according to the joint analysis, but were seemingly cell type-specific by the tissue-by-tissue analysis. The genes with such notable patterns include CTLA4, known for its inhibitory role in T cell mediated immune responses and association with many organ-specific autoimmune diseases[29]. The autoimmunity-susceptible SNPs in this region( rs231775, rs3087243, and rs231806) have been associated with various functional effects including CTLA4 transcript levels, splicing, production of the soluble form of CTLA-4 and posttranslational modifications[28, 43–45]. In addition, our results show differential DNA methylation in the CTLA4 region to be associated with the potential isoform-specific differences in CD4+ and CD8+ T cells. This is likely due to negative correlation between DNA methylation and gene expression, which eventually leads to lower expression levels and moderate effect sizes. To confirm whether the observed effects are due to true differences in isoforms instead of the quality of the designed probes at capturing variation in gene expression levels, a follow-up study with RNA-seq data is needed. The observed trans-acting regulatory region on chr12q13. 2 in CD4+ and CD8+ T cells indicates the important role of genetic variants in that region affecting the expression levels of over a hundred genes across the genome. Interestingly, the region includes the RPS26 gene, which may constitute a mechanism for the detected trans-eQTL effects. Our lead SNP rs1131017 is located in an oligopyrimidine tract of the 5´UTR of the RPS26 mRNA and its T1D risk allele rs1131017[C] correlates positively with RPS26 expression levels[46, 47]. The oligopyrimidine tract controls the translation of many mammalian ribosomal protein genes[48], and the effect of the SNP on RPS26 ribosomal distribution has been reported[49]. RPS26 is a main component of the ribosomal region involved in the recruitment of cellular mRNA during translational initiation and in maintenance of the path of mRNA molecules to the ribosomal exit site[50]. Hence, it is conceivable that changed RPS26 protein levels may affect the stability or translational efficiency of a large number of cytosolic mRNAs. Nevertheless, the exact functional role of rs1131017[C] in T1D remains to be identified, as well as the effect of other candidate genes in this region such as IKZF4, ERBB3[51] and CDK2[52]. Strikingly, we identified a common missense variant in cytokine IL27 as a significant trans-eQTL for IRF1 and STAT1 in CD4+ T cells. The effect of IL-27 in T cells is regarded as anti-inflammatory but it has also been shown as a growth and survival factor for T cells[42]. As a heterodimer with EBI3, IL-27 activates the STAT1/STAT3 pathway that induces the transcription of several interferon-induced genes, including IRF1 and STAT1 itself. Our model suggests that IRF1 mediates the effect of the IL27 SNP on expression levels of STAT1. Moreover, our functional studies with the mutated form of IL-27 confirmed its decreased capacity to activate the STAT1 pathway, and we showed that a potential causal variant( the missense variant rs181206) for T1D susceptibility and changes in IRF1 and STAT1 expression is shared. Furthermore, our findings are supported by studies of a T1D mouse model with high levels of IL-27 and delayed T1D onset after treatment with an IL-27 blocking antibody[53]. Altogether these results suggest that the rs181206[G] variant of the IL27 gene confers protection against T1D through the inhibited expression of IRF1 and STAT1 in CD4+ T cells. Our results also suggest that IL-27 may promote autoimmunity toward pancreatic islets via the upregulation of the STAT1 pathway. In conclusion, the analysis of genetic modulators of gene expression profiles as intermediate phenotypes between human traits and underlying genetic variation offers new instruments to refine our understanding of disease susceptibility. Moreover, eQTL studies in purified cell types instead of whole blood enable us to establish the specific mechanisms and pathways involved in diseases progression and create the basis for future explorations and drug interventions.
Variation in regulatory regions as well as coding regions of the genome can affect the expression of genes . Many of these variants have been associated with different diseases and other traits , but the underlying biological pathways are often left unknown . Analysing the effect of single nucleotide polymorphisms ( SNPs ) on gene expression levels , referred to as expression quantitative trait loci ( eQTL ) , in specific cell types can be used to gain insight into specific mechanisms of disease . By analyzing eQTLs in CD4+ and CD8+ T cells , essential elements of adaptive immune response , we identified both cis- and trans-acting SNPs in genes associated with several autoimmune diseases .