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Blood vessels are continually exposed to circulating lipids, and elevation of ApoB-containing lipoproteins causes atherosclerosis. Lipoprotein metabolism is highly regulated by lipolysis, largely at the level of the capillary endothelium lining metabolically active tissues. How large blood vessels, the site of atherosclerotic vascular disease, regulate the flux of fatty acids (FAs) into triglyceride-rich (TG-rich) lipid droplets (LDs) is not known. In this study, we showed that deletion of the enzyme adipose TG lipase (ATGL) in the endothelium led to neutral lipid accumulation in vessels and impaired endothelialdependent vascular tone and nitric oxide synthesis to promote endothelial dysfunction. Mechanistically, the loss of ATGL led to endoplasmic reticulum stress-induced inflammation in the endothelium. Consistent with this mechanism, deletion of endothelial ATGL markedly increased lesion size in a model of atherosclerosis. Together, these data demonstrate that the dynamics of FA flux through LD affects endothelial cell homeostasis and consequently large vessel function during normal physiology and in a chronic disease state., Introduction The vascular endothelium is essential in lipid partitioning (1). Specifically, in metabolically active tissues (e.g., heart, skeletal muscle, adipose), triglyceride-rich (TG-rich) lipoproteins (chylomicrons, VLDL) are metabolized by lipoprotein lipase [...]

Inflammation is a beneficial host response to infection but can contribute to inflammatory disease if unregulated. The TH17 lineage of T helper (Th) cells can cause severe human inflammatory diseases. These cells exhibit both instability (they can cease to express their signature cytokine, IL-17A) (1) and plasticity (they can start expressing cytokines typical of other lineages) (1,2) upon in vitro re-stimulation. However, technical limitations have prevented the transcriptional profiling of pre- and post-conversion TH17 cells ex vivo during immune responses. Thus, it is unknown whether TH17 cell plasticity merely reflects change in expression of a few cytokines, or if TH17 cells physiologically undergo global genetic reprogramming driving their conversion from one T helper cell type to another, a process known as transdifferentiation (3,4). Furthermore, although TH17 cell instability/plasticity has been associated with pathogenicity (1,2,5), it is unknown whether this could present a therapeutic opportunity, whereby formerly pathogenic TH17 cells could adopt an anti-inflammatory fate. Here we used two new fate-mapping mouse models to track TH17 cells during immune responses to show that [CD4.sup.+] T cells that formerly expressed IL-17A go on to acquire an antiinflammatory phenotype. The transdifferentiation of TH17 into regulatory T cells was illustrated by a change in their signature transcriptional profile and the acquisition of potent regulatory capacity. Comparisons of the transcriptional profiles of pre- and post-conversion TH17 cells also revealed a role for canonical TGF-β signalling and consequently for the aryl hydrocarbon receptor (AhR) in conversion. Thus, TH17 cells transdifferentiate into regulatory cells, and contribute to the resolution of inflammation. Our data suggest that TH17 cell instability and plasticity is a therapeutic opportunity for inflammatory diseases., TH17 cells are characterized by secretion of IL-17A, expression of chemokine receptor CCR6 and transcriptional factor RORγt (6). Their pathogenicity is limited by [Foxp3.sup.+] [T.sub.Reg] and T regulatory type 1 [...]

Interleukin (IL)-17-producing T helper cells ([T.sub.H]17) are a recently identified [CD4.sup.+] T cell subset distinct from T helper type 1 ([T.sub.H]1) and T helper type 2 ([T.sub.H]2) cells (1). [T.sub.H]17 cells can drive antigenspecific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE) (2), the mouse model for multiple sclerosis. The factors that are needed for the generation of [T.sub.H]17 cells have been well characterized (3-6). However, where and how the immune system controls [T.sub.H]17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory [T.sub.H]17 cells can be redirected to and controlled in the small intestine. [T.sub.H]17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that [T.sub.H]17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory [T.sub.H]17 cells simultaneously acquire a regulatory phenotype with invitro and invivoimmune-suppressive properties (r[T.sub.H]17). These results identify mechanisms limiting [T.sub.H]17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of [T.sub.H]17 cells., [T.sub.H]17 cells have been associated with the pathogenesis of several chronic inflammatory disorders, including rheumatoid arthritis and multiple sclerosis (2,7). To study the cellular and molecular mechanisms that control pathogenicity [...]

Growing insight into the pathogenesis of autoimmune diseases and numerous studies in preclinical models highlights the potential of regulatory T cells to restore tolerance. By using non-obese diabetic (NOD) BDC2.5 TCR-transgenic (Tg), and IL-10 and Foxp3 doublereporter mice, we demonstrate that alteration of gut microbiota during cohousing experiments or treatment with anti-CD3 mAb significantly increase intestinal IL-10-producing type 1 regulatory T (Tr1) cells and decrease diabetes incidence. These intestinal antigenspecific Tr1 cells have the ability to migrate to the periphery via a variety of chemokine receptors such as CCR4, CCR5, and CCR7 and to suppress proliferation of Th1 cells in the pancreas. The ability of Tr1 cells to cure diabetes in NOD mice required IL-10 signaling, as Tr1 cells could not suppress CD4+ T cells with a dominant-negative IL-10R. Taken together, our data show a key role of intestinal Tr1 cells in the control of effector T cells and development of diabetes. Therefore, modulating gut-associated lymphoid tissue to boost Tr1 cells may be important in type 1 diabetes management. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigenpresenting cells, dendritic cells. Applying intravital two-photon microscopy, we demonstrate the gatekeeper function of CNS professional antigen-presenting CD11c+ cells, which preferentially interact with Th17 cells. IL-17 expression correlates with expression of GM-CSF by T cells and with accumulation of CNS CD11c+ cells. These CD11c+ cells are organized in perivascular clusters, targeted by T cells, and strongly express the inflammatory chemokines Ccl5, Cxcl9, and Cxcl10. Our findings demonstrate a fundamental role of CNS CD11c+ cells in the attraction of pathogenic T cells into and their survival within the CNS. Depletion of CD11c+ cells markedly reduced disease severity due to impaired enrichment of pathogenic T cells within the CNS. [ABSTRACT FROM AUTHOR]

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 immunemediated 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. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells. TH17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of TH17 cells have been well characterized. However, where and how the immune system controls TH17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine. TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory TH17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17). These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells. [ABSTRACT FROM AUTHOR]