IL-10 Locus Research Articles

Aiolos promotes TH17 differentiation by directly silencing Il2 expression

CD4(+) interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are instrumental in the immune response to pathogens. However, an overactive T(H)17 response results in tissue inflammation and autoimmunity, and therefore it is important to identify the molecular mechanisms that control the development of T(H)17 cells. IL-2 suppresses such development, but how IL-2 production is actively suppressed during T(H)7 differentiation is not understood. Here we report that under T(H)17-polarizing conditions, the transcription factors STAT3 and AhR upregulated the expression of Aiolos, a member of the Ikaros family of transcription factors. Using Aiolos-deficient mice, we demonstrated that Aiolos silenced the Il2 locus, promoting T(H)17 differentiation in vitro and in vivo. Thus, we have identified a module in the transcriptional program of T(H)17 cells that actively limits IL-2 production and promotes their differentiation.

A protective role for human IL-10-expressing CD4+ T cells in colitis (121.11)

Abstract Little is known about the relationship between cell- or tissue-specific IL-10 expression and disease susceptibility in humans. Here, we utilized the previously described hIL10BAC transgenic model to examine the role of human IL-10 (hIL-10) in maintaining intestinal homeostasis. Genomically-controlled hIL-10 expression rescued Il10−/− mice from Helicobacter-induced colitis and was associated with control of pro-inflammatory cytokine expression and TH17 cell accumulation in gut tissues. Resistance to colitis was associated with an accumulation of hIL-10-expressing CD4+Foxp3+ T regulatory cells specifically within the lamina propria but not other secondary lymphoid tissues. Co-transfer of CD4+CD45RBlo cells from Il10-/-/hIL10BAC mice rescued Rag1-/- mice from colitis further suggesting that CD4+ T cells represent a protective source of hIL-10 in the colon. In concordance with an enhanced capacity to express IL-10, CD4+CD44+ T cells isolated from the lamina propria exhibited lower levels of the repressive histone mark H3K27Me3 and higher levels of the permissive histone mark AcH3 in both the human and mouse IL10 locus compared to the spleen. These results provide experimental evidence verifying the importance of T cell-derived human IL-10 expression in controlling inflammation within the colonic mucosa. We also provide molecular evidence suggesting the tissue microenvironment influences IL-10 expression patterns and chromatin structure in the human (and mouse) IL10 locus.

Signals through GITR program CD4+ T cells to induce interleukin-9 (163.9)

Abstract Glucocorticoid-induced TNF receptor family-related protein (GITR) is expressed on various immune cells and well known as one of the co-stimulatory molecules to promote T helper (Th) type 2 responses. In this study, we show that an agonistic anti-GITR mAb (clone DTA-1) induced IL-9 production on the committing Th2 and regulatory T (Treg) cells, as well as enhanced IL-9 production from naive CD4+ T cells under Th9 skewing condition. Whereas, DTA-1 did not induce IFN-γ or IL-17A, lineage-specific cytokines of Th1 or Th17, respectively and was resistant to produce IL-9 from naive CD4 T cells under Th1 or Th17 polarizing conditions. Furthermore, GITR stimulation promoted reprogramming of regulatory T cells to produce IL-9+Foxp3+ Treg and effector Th9 cells. We found transcription factor Interferon-regulatory factor4 (IRF4) was up-regulated by GITR ligation at the early stage of Th9 differentiation and contributed to enhance IL-9 production. Also, when GITR signaling was activated, p65, activated by NFκB signaling pathways, directly interacted with Il9 locus including promoter region at the later stage of Th9 differentiation. Consistent with in vitro study, in vivo administration of DTA-1 enhanced IL-9 at the transcript level and the roles of IL-9 induced by GITR ligation in vivo are remained to be investigated for further studies.

Production of IL-17

Th17 cells are important mediators of autoimmunity, yet the mechanisms by which they are controlled are not fully understood. Studies in mice, including a recent article in Nature Immunology by Yang et al., show that IL-2 is an important inhibitory factor for the differentiation of Th17 cells, inducing phosphorylation of STAT5, which outcompetes STAT3 binding at the IL-17 locus. In humans however, IL-2 appears to be crucial for Th17 differentiation, yet inhibits the expansion of antigen-specific Th17 clones, again via a STAT5 mechanism. Here we discuss how the article by Yang et al. offers a novel mechanism to explain how changes in the balance of different cytokines in the inflammatory environment may alter the stability or phenotype of regulatory T cells and T helper cell subsets.

Irritable Bowel Syndrome: Methods, Mechanisms, and Pathophysiology. Genetic epidemiology and pharmacogenetics in irritable bowel syndrome

The objectives of this review are twofold. Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome (IBS). Specific examples of the associations of genetic variation and symptoms, syndromes, and intermediate phenotypes, including neurotransmitter (serotonergic, α(2)-adrenergic, and cannabinoid) mechanisms, inflammatory pathways (IL-10, TNFα, GNβ3, and susceptibility loci involved in Crohn's disease), and bile acid metabolism, are explored. The second objective is to review pharmacogenetics in IBS, with the focus on cytochrome P-450 metabolism of drugs used in IBS, modulation of motor and sensory responses to serotonergic agents based on the 5-hydroxytryptamine (5-HT) transporter-linked polymorphic region (5-HTTLPR) and 5-HT(3) genetic variants, responses to a nonselective cannabinoid agonist (dronabinol) based on cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) variation, and responses to a bile acid (sodium chenodeoxycholate) and bile acid binding (colesevelam) based on klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) variation. Overall, there is limited evidence of a genetic association with IBS; the most frequently studied association is with 5-HTTLPR, and the most replicated association is with TNF superfamily member 15. Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials, and confirmation in large clinical trials using validated clinical end points is still required. No published genome-wide association studies in functional gastrointestinal or motility disorders have been published.

IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme

BackgroundSWI/SNF chromatin remodeling enzymes play a critical role in the development of T helper lymphocytes, including Th2 cells, and directly program chromatin structure at Th2 cytokine genes. Different versions of SWI/SNF complexes, including BAF and PBAF, have been described based on unique subunit composition. However, the relative role of BAF and PBAF in Th cell function and cytokine expression has not been reported.ResultsHere we examine the role of the PBAF SWI/SNF complex in Th cell development and gene expression using mice deficient for a PBAF-specific component, BAF180. We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus.ConclusionsThese results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.

Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort

ObjectiveA number of rheumatoid arthritis (RA) susceptibility genes have been identified in recent years. Given the overlap in phenotypic expression of synovial joint inflammation between RA and psoriatic arthritis (PsA),...

Interleukin-4 Production by Follicular Helper T Cells Requires the Conserved Il4 Enhancer Hypersensitivity Site V

Follicular helper T cells (Tfh cells) are the major producers of interleukin-4 (IL-4) in secondary lymphoid organs where humoral immune responses develop. Il4 regulation in Tfh cells appears distinct from the classical T helper 2 (Th2) cell pathway, but the underlying molecular mechanisms remain largely unknown. We found that hypersensitivity site V (HS V; also known as CNS2), a 3' enhancer in the Il4 locus, is essential for IL-4 production by Tfh cells. Mice lacking HS V display marked defects in type 2 humoral immune responses, as evidenced by abrogated IgE and sharply reduced IgG1 production in vivo. In contrast, effector Th2 cells that are involved in tissue responses were far less dependent on HS V. HS V facilitated removal of repressive chromatin marks during Th2 and Tfh cell differentiation and increased accessibility of the Il4 promoter. Thus, Tfh and Th2 cells utilize distinct but overlapping molecular mechanisms to regulate Il4, a finding with important implications for understanding the molecular basis of allergic diseases.

Cytokine Gene Polymorphisms and Human Autoimmune Disease in the Era of Genome-Wide Association Studies

Cytokine (receptor) genes have traditionally attracted great interest as plausible genetic risk factors for autoimmune disease. Since 2007, the implementation of genome-wide association studies has facilitated the robust identification of allelic variants in more than 35 cytokine loci as susceptibility factors for a wide variety of over 15 autoimmune disorders. In this review, we catalog the gene loci of interleukin, chemokine, and tumor necrosis factor receptor superfamily and ligands that have emerged as autoimmune risk factors. We examine recent progress made in the clarification of the functional mechanisms by which polymorphisms in the genes coding for interleukin-2 receptor alpha (IL2RA), IL7R, and IL23R may alter risk for autoimmune disease, and discuss opposite autoimmune risk alleles found, among others, at the IL10 locus.

C-Myb and GATA-3 Cooperatively Regulate IL-13 Expression via Conserved GATA-3 Response Element and Recruit Mixed Lineage Leukemia (MLL) for Histone Modification of the IL-13 Locus

The c-Myb and GATA-3 transcription factors play important roles in T cell development. We recently reported that c-Myb, GATA-3, and Menin form a core transcription complex that regulates GATA-3 expression and ultimately Th2 cell development in human peripheral blood T cells. However, c-Myb roles for Th2 cytokine expression were not demonstrated. In this article, we report that c-Myb and GATA-3 cooperatively play an essential role in IL-13 expression though direct binding to a conserved GATA-3 response element (CGRE), an enhancer for IL-13 expression. c-Myb and GATA-3 were shown to activate the CGRE-IL-13 promoter by ∼160-fold, and mutation of the canonical Myb binding site completely abrogated CGRE enhancer activity. In contrast, mutation of the GATA binding site partially decreased CGRE enhancer activity. GATA-3 did not bind to CGRE when c-myb expression was silenced. c-Myb, GATA-3, Menin, and mixed lineage leukemia (MLL) bound to CGRE in human primary CD4(+) effector/memory cells. Moreover, c-myb silencing significantly decreased both methylation of histone H3K4 and acetylation of histone H3K9 at the IL-13 locus in CD4(+) effector/memory cells. Therefore, in addition to the strong enhancer effect for the transcription of IL-13, the c-Myb/GATA-3 complex recruits MLL to the CGRE for histone modification of the IL-13 locus during the differentiation of memory Th2 cells.

Association of an Anti-inflammatory Cytokine Gene IL4 Polymorphism with the Risk of Type 2 Diabetes Mellitus in Korean Populations

Chronic inflammation has been implicated as one of the important etiological factors in insulin resistance and type 2 diabetes mellitus (T2DM). To investigate the role of anti-inflammatory cytokines in the development of T2DM, we conducted a case-control study to assess the association between IL4/IL4R polymorphisms and disease risk. We firstly identified single nucleotide polymorphisms (SNP) at IL4 and IL4RA loci by sequencing the loci in Korean participants. Case-control studies were conducted by genotyping the SNPs in 474 T2DM cases and 470 non-diabetic controls recruited from community-based cohorts. Replication of the associated signals was performed in 1,216 cases and 1,352 controls. We assessed effect of IL4-IL4RA interaction on T2DM using logistic regression method. The functional relevance of the SNP associated with disease risk was determined using a reporter expression assay. We identified a strong association between the IL4 promoter variant rs2243250 and T2DM risk (OR=0.77; 95% CI, 0.67∼0.88; p=1.65×10 －4 in the meta-analysis). The reporter gene expression assay demonstrated that the presence of rs2243250 might affect the gene expression level with ∼1.5-fold allele difference. Our findings contribute to the identification of IL4 as a T2D susceptibility locus, further supporting the role of anti-inflammatory cytokines in T2DM disease development.

Two-Step Binding of Transcription Factors Causes Sequential Chromatin Structural Changes at the Activated IL-2 Promoter

Most gene promoters have multiple binding sequences for many transcription factors, but the contribution of each of these factors to chromatin remodeling is still unclear. Although we previously found a dynamic change in the arrangement of nucleosome arrays at the Il2 promoter during T cell activation, its timing preceded that of a decrease in nucleosome occupancy at the promoter. In this article, we show that the initial nucleosome rearrangement was temporally correlated with the binding of NFAT1 and AP-1 (Fos/Jun), whereas the second step occurred in parallel with the recruitment of other transcription factors and RNA polymerase II. Pharmacologic inhibitors for activation of NFAT1 or induction of Fos blocked the initial phase in the sequential changes. This step was not affected, however, by inhibition of c-Jun phosphorylation, which instead blocked the binding of the late transcription factors, the recruitment of CREB-binding protein, and the acetylation of histone H3 at lysine 27. Thus, the sequential recruitment of transcription factors appears to facilitate two separate steps in chromatin remodeling at the Il2 locus.

Critical Role of TCF-1 in Repression of the IL-17 Gene

Overwhelming activation of IL-17, a gene involved in inflammation, leads to exaggerated Th17 responses associated with numerous autoimmune conditions, such as experimental autoimmune encephalomyelitis (EAE). Here we show that TCF-1 is a critical factor to repress IL-17 gene locus by chromatin modifications during T cell development. Deletion of TCF-1 resulted in increased IL-17 gene expression both in thymus and peripheral T cells, which led to enhanced Th17 differentiation. As a result, TCF-1-/- mice were susceptible to Th17-dependent EAE induction. Rag1-/- mice reconstituted with TCF-1-/- T cells were also susceptible to EAE, indicating TCF-1 is intrinsically required to repress IL-17. However, expression of wild-type TCF-1 or dominant negative TCF-1 did not interfere with Th17 differentiation in mature T cells. Furthermore, expression of TCF-1 in TCF-1-/- T cells could not restore Th17 differentiation to wild-type levels, indicating that TCF-1 cannot affect IL-17 production at the mature T cell stage. This is also supported by the normal up-regulation or activation in mature TCF-1-/- T cells of factors known to regulate Th17 differentiation, including RORγt and Stat3. We observed hyperacetylation together with trimethylation of Lys-4 at the IL-17 locus in TCF-1-/- thymocytes, two epigenetic modifications indicating an open active state of the gene. Such epigenetic modifications were preserved even when TCF-1-/- T cells migrated out of thymus. Therefore, TCF-1 mediates an active process to repress IL-17 gene expression via epigenetic modifications during T cell development. This TCF-1-mediated repression of IL-17 is critical for peripheral T cells to generate balanced immune responses.

Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease

Dysregulated CD4(+) T cell responses and alterations in T regulatory cells (T(reg) cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in T(reg) cells causes IBD because of proinflammatory cytokine-producing CD4(+) T cells infiltrating the colon. Provision of WT T(reg) cells prevented IBD, demonstrating that alterations in T(reg) cells are responsible for the disease. Furthermore, Bcl11b-deficient T(reg) cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b altered the induction of Foxp3 expression and reduced the generation of induced T(reg) cells (iT(reg) cells) after Tgf-β treatment of conventional CD4(+) T cells. Bcl11b bound to Foxp3 and IL-10 promoters, as well as to critical conserved noncoding sequences within the Foxp3 and IL-10 loci, and mutating the Bcl11b binding site in the Foxp3 promoter reduced expression of a luciferase reporter gene. These experiments demonstrate that Bcl11b is indispensable for T(reg) suppressor function and for maintenance of optimal Foxp3 and IL-10 gene expression, as well as for the induction of Foxp3 expression in conventional CD4(+) T cells in response to Tgf-β and generation of iT(reg) cells.

Replication of Genetic Association Studies in Aortic Stenosis in Adults

Only a handful of studies have attempted to unravel the genetic architecture of calcific aortic valve stenosis (AS). The goal of this study was to validate genes previously associated with AS. Seven genes were assessed: APOB, APOE, CTGF, IL10, PTH, TGFB1, and VDR. Each gene was tested for a comprehensive set of single-nucleotide polymorphisms (SNPs). SNPs were genotyped in 457 patients who underwent surgical aortic valve replacement, and allele frequencies were compared to 3,294 controls. A missense mutation in the APOB gene was significantly associated with AS (rs1042031, E4181K, p = 0.00001). A second SNP located 5.6 kilobases downstream of the APOB stop codon was also associated with the disease (rs6725189, p = 0.000013). Six SNPs surrounding the IL10 locus were strongly associated with AS (0.02 > p > 6.2 × 10⁻¹¹). The most compelling association for IL10 was found with a promoter polymorphism (rs1800872) well known to regulate the production of the encoded anti-inflammatory cytokine. The frequency of the low-producing allele was greater in cases compared to controls (30% vs 20%, p = 6.2 × 10⁻¹¹). SNPs in PTH, TGFB1, and VDR had nominal p values <0.05 but did not resist Bonferroni correction. In conclusion, this study suggests that subjects carrying specific polymorphisms in the IL10 and APOB genes are at higher risk for developing AS.

Inflamed gut mucosa: downstream of interleukin‐10

Interleukin-10 is a pleiotropic cytokine, whose main function is limitation and ultimately termination of immune responses. This is especially true for environmental interfaces such as the gastrointestinal tract. IL-10 acts as a key mediator for maintaining gut homeostasis. IL-10 knockout mice are well established as a genetic model for inflammatory bowel disease (IBD), and sequence variants in the IL-10 locus contribute to ulcerative colitis (UC). This review covers the significance of IL-10 signalling in the intestinal immune response both in health and disease. It explains the biological role of IL-10, its deregulation in IBD and its contribution to intestinal inflammation via endoplasmic reticulum stress response. Many IBD susceptibility genes have been discovered in the past years, linking fundamental biological systems, like innate and adaptive immunity, stress responses, autophagy and mucosal barrier to the pathogenesis of Crohn's disease (CD) and UC. IL-10 has long been known for its substantial role in regulating gut immunity, but its contribution to IBD was somewhat elusive. A recent study identified mutations in either IL-10 receptor subunits that are associated with early-onset enterocolitis, a severe phenotype of IBD. Other than genetic variants of IL-10 receptors, IL-10 and STAT3 genes are also associated with IBD, emphasizing the involvement of the IL-10 signalling cascade in the pathogenesis of CD and UC. The discovery of inherited deregulations in the IL-10 signalling cascade is not only considered the missing link between IL-10 and intestinal homeostasis, but also demonstrates how findings made in animal models help explaining human disease.

Genetic predisposition to parthenium dermatitis in an Indian cohort due to lower-producing genotypes of interleukin-10 (−) 1082 G&gt;A and (−) 819 C&gt;T loci but no association with interferon-γ (+) 874 A&gt;T locus

Parthenium dermatitis is an activated T cell-mediated type IV hypersensitivity. Its pathogenesis is well characterized, with interindividually varying serum levels of pro- and anti-inflammatory and regulatory T-cell cytokines and coherently perturbed cross-regulation between them. The functional single nucleotide polymorphisms (SNPs) in these cytokine genes might function as risk/susceptibility factors for the disease. We analysed the serum levels of interferon (IFN)-γ and interleukin (IL)-10 cytokines in cases vs. controls and investigated whether IFN-γ (+) 874 A>T and IL-10 (-) 1082 G > A and (-) 819 C>T are associated with serum levels and genetically predispose to the disease. The study included 60 patch test-confirmed patients and 60 age- and sex-matched controls. The serum levels of cytokines were estimated by high-sensitivity enzyme-linked immunosorbent assay kits. SNP genotyping was performed by amplification refractory mutational system-polymerase chain reaction. In patients, the serum level of IFN-γ was significantly increased and that of IL-10 was significantly decreased, with no difference in IgE concentration. Genetically no IFN-γ (+) 874 A>T alleles/genotypes were associated with the disease, but a strong predisposition was found due to lower-producing genotypes of IL-10 (-) 1082 G>A and (-) 819 C>T SNPs, with 2·1 and 3·5 times more risk, respectively, while intermediate IL-10-producing genotypes provided resistance. High serum IFN-γ might play a role in disease pathogenesis, but this is genetically not endowed by the IFN-γ SNP studied. In contrast, low serum IL-10 was very much connected, with the genetics of both studied IL-10 loci. These might be key managing factors concerning pathogenesis/susceptibility.

Punctate Inner Choroidopathy and Multifocal Choroiditis with Panuveitis Share Haplotypic Associations withIL10andTNFLoci

The white-dot syndromes are a heterogenous group of chorioretinal disorders that have many common clinical features. Whether these disorders represent distinct clinical entities or different manifestations of the same disease warrants further interrogation. Two white-dot syndromes were investigated, with closely overlapping phenotypes--multifocal choroiditis with panuveitis (MFCPU) and punctate inner choroidopathy (PIC)--for differences in clinical course and genotype frequency at IL10 and TNF loci, known to be associated with noninfectious uveitis. Twelve polymorphisms were genotyped, spanning the TNFA and IL10 genomic regions, in 61 patients with MFCPU or PIC and 92 population controls from the United Kingdom and Republic of Ireland. There were clear differences in clinical course between patients with MFCPU and PIC which had prognostic significance. However, both patient groups demonstrated similar associations with the IL10 haplotype, IL10htSNP2(-2849)AX/htSNP5(+434)TC and negative associations with the TNF haplotype, LTA+252A/TNFhtSNP1(-308)G/TNFhtSNP2(-238)G/TNFhtSNP3(+488)A/TNFd3. Despite clear differences in clinical course and outcome, MFCPU and PIC may still represent two manifestations of the same disease, given their similar genetic associations with IL10 and TNF loci, which are known to be associated with noninfectious uveitis and autoimmunity, in general. Definitive proof will necessitate genomewide sequence analysis. However, the data also support the notion that epigenetic factors have a strong effect on clinical phenotype.

PU.1 regulates chromatin modifications of the Il9 gene in Th9 cells (57.5)

Abstract IL-9-secreting Th9 cells are generated when naïve CD4+ T cells are cultured with IL-4 and TGF-β. The transcription factor, PU.1 is required for the development of Th9 cells. The expression of PU.1, which is abundantly expressed in Th9 cells, is dependent on TGF-β dose. Dose dependent increase in TGF-β leads to a concomitant increase in PU.1 expression and IL-9 production. Ectopic expression of PU.1 can convert Th2 cells to Th9 phenotype and enhance IL-9 production from Th9 cells. The DNA binding domain and the transactivation domains of PU.1 are required for PU.1 to activate Il9, suggesting that as it binds Il9, it recruits other factors to mediate gene activation. We hypothesized that PU.1 recruits specific chromatin modifying enzymes to the Il9 locus. H3 acetylation is decreased in PU.1-deficient Th9 cells on both the Il9 promoter and a second conserved non-coding sequence immediately after 3’ of the Il9 gene. H3K9/18 acetylation is also diminished in PU.1-deficient Th9 cells while H4 acetylation is not altered by PU.1-deficiency demonstrating specific PU.1-mediated histone modifications correlating with Il9 transcription. Overall these results indicate that PU.1 promotes expression of IL-9 by modifying specific histones at the Il9 locus.

Protein phosphatase 2A facilitates IL-17 production by promoting accessibility to the IL-17 locus (47.15)

Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease caused by the combination of several immune abnormalities. T cells from SLE patients exhibit an aberrant phenotype, caused in part by increased levels of the protein phosphatase 2A (PP2A). To study the mechanisms through which PP2A alters T cell behavior and to identify the contribution of this defect to the disease, we generated a transgenic mouse that over-expresses PP2A in T cells. The transgenic mice produced abnormally high levels of IL-17A and F in vivo and in vitro. Remarkably, naïve CD4+ TPP2A cells produced IL-17 as early as 3h after stimulation. This effect was specific for IL-17 as production of type I and type II cytokines was not affected. PP2A over-expression did not promote Th17 differentiation or significant increases in Th17-related transcription factors. Due to the specificity of the phenomenon and its kinetics, we hypothesized that PP2A may facilitate transcription in the IL-17 locus. ChIP experiments revealed increased tri-methylation of H3K4 and decreased tri-methylation of H3K9 at the Il17a and Il17f promoters as well as in local conserved non-coding sequences. These changes are associated with increased chromatin accessibility. We propose that PP2A plays a central role in the transcriptional regulation of IL-17 by promoting chromatin accessibility to the IL-17 locus. This pathway may play a role in the excessive IL-17 production observed in SLE T cells.