IL-27-Induced Type 1 Regulatory T-Cells Produce Oxysterols that Constrain IL-10 Production

IF 6.429International audienceThe behaviors of lymphocytes, including CD4(+) T helper cells, are controlled on many levels by internal metabolic properties. Lipid metabolites have recently been ascribed a novel function as immune response modulators and perturbation of steroids pathways modulates inflammation and potentially promotes a variety of diseases. However, the impact of lipid metabolism on autoimmune disease development and lymphocyte biology is still largely unraveled. In this line, oxysterols, oxidized forms of cholesterol, have pleiotropic roles on the immune response aside from their involvements in lipid metabolism. The oxysterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC) regulate antiviral immunity and immune cell chemotaxis. However, their physiological effects on adaptive immune response in particular on various subset CD4(+) T lymphocytes are largely unknown. Here, we assessed oxysterol levels in subset of CD4(+) T cells and demonstrated that 25-OHC and transcript levels of its synthesizing enzyme, cholesterol 25-hydroxylase, were specifically increased in IL-27-induced type 1 regulatory T (TR1) cells. We further showed that 25-OHC acts as a negative regulator of TR1 cells in particular of IL-10 secretion via liver X receptor signaling. Not only do these findings unravel molecular mechanisms accounting for IL-27 signaling but also they highlight oxysterols as pro-inflammatory mediators that dampens regulatory T cell responses and thus unleash a pro-inflammatory response

A single nucleotide polymorphism in the gene for GPR183 increases its surface expression on blood lymphocytes of patients with inflammatory bowel disease.

The single nucleotide polymorphism rs9557195 within the gene Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) has been associated with increased risk for inflammatory bowel diseases (IBD). EBI2 mediates migration of intestinal immune cells and promotes colitis in animal models. Here we study EBI2 surface expression of immune cells and associations of rs9557195 with EBI2 expression and IBD disease course. We recruited 27 IBD patients (15 with ulcerative colitis (UC), 12 with Crohn's disease (CD)), and 8 healthy volunteers (HV). EBI2 expression was measured by fluorescence activated cell sorting in subtypes of peripheral blood mononuclear cells. We further analyzed IBD disease course in 2301 patients (1335 with CD and 966 with UC) of the Swiss IBD cohort study (SIBDCS). We found increased EBI2 expression in lymphocytes expressing chemokine receptors CCR6 or CCR9, implicated in IBD and on Th17 memory T cells. The EBI2 ligand 7α,25-dihydroxycholesterol and the CCR6 ligand CCL20 stimulated migration of memory T cells in an additive manner. Further, IBD patients with the CC allele of rs9557195 had higher EBI2 surface expression compared to individuals with the TT allele. SIBDC patients carrying the rs9557195-CC allele had higher psoriasis rates compared to individuals with the TT allele. We demonstrate increased EBI2 surface expression on T cells with a potential role in gut inflammation. A SNP of the EBI2 locus was associated with EBI2 surface expression and psoriasis rates in IBD patients. Our data suggest a pro-inflammatory role of EBI2 in IBD

A single nucleotide polymorphism in the gene for GPR183 increases its surface expression on blood lymphocytes of patients with inflammatory bowel disease

Background and purpose: Single nucleotide polymorphism rs9557195 within the gene of the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2/GPR183) has been associated with increased risk for inflammatory bowel diseases (IBD). GPR183 mediates the migration of intestinal immune cells and promotes colitis in animal models. Here, we study GPR183 surface expression of immune cells and associations of rs9557195 with GPR183 expression and IBD disease course. Experimental approach: We recruited 27 IBD patients (15 with ulcerative colitis [UC] and 12 with Crohn's disease [CD]) and eight healthy volunteers (HV). GPR183 expression was measured by FACS in subtypes of peripheral blood mononuclear cells. We analysed IBD disease course in 2301 patients (1335 with CD and 966 with UC) of the Swiss IBD cohort study. Key results: We found increased GPR183 expression in lymphocytes expressing chemokine receptors CCR6 or CCR9, implicated in IBD and on Th17 memory T cells. The GPR183 ligand 7α,25-dihydroxycholesterol and the CCR6 ligand CCL20 stimulated migration of memory T cells in an additive manner. Further, IBD patients with the CC allele of rs9557195 had higher GPR183 surface expression compared to individuals with the TT allele. Swiss IBD cohort study patients carrying the rs9557195-CC allele had higher psoriasis rates compared to individuals with the TT allele. Conclusion and implications: We demonstrate increased GPR183 surface expression on T cells with a potential role in gut inflammation. An SNP of the GPR183 locus was associated with GPR183 surface expression and psoriasis rates in IBD patients. Our data suggest a pro-inflammatory role of GPR183 in IBD. Linked articles: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc. Keywords: FACS; GPR183/EBI2; IBD; SNP; UBAC2; psoriasis