Intestinal RORrt-generated Th17 cells control type 2 diabetes: A first antidiabetic target identified from the host to microbiota crosstalk

The recent discovery of the role played by gut microbiota on the control of metabolic disease opens novel routes for the identification of the causes of type 2 diabetes and obesity. This paradigm could explain the infiltration, by innate and adaptive immune cells, of the adipose tissue, liver, and islets of Langerhans which is responsible for the metabolic inflammation state that leads to impaired insulin action and secretion, and therefore, type 2 diabetes. The identification of the causal role of circulating lipopolysaccharides LPS and peptidoglycans in the development of metabolic inflammation, due to an increased intestinal permeability, led to the leaky gut hypothesis. In addition, whole live bacteria were found in metabolic tissues establishing a tissue microbiota which upon a fat-enriched diet becomes dysbiotic. The process of intestinal bacterial translocation was responsible for the onset of a leaky gut causal to the disease. The translocation of selective sets of intestinal bacteria to the blood could be identified. These blood bacterial 16SrRNA-DNA sequences are considered as biomarkers of the bacterial translocation process. An increased of the corresponding bacterial DNA concentration was predicting the occurrence of type 2 diabetes. Associated to the dysbiotic microbiota translocation, an impaired intestinal immune defense was identified as a cause of the selective leaky gut. The change in small intestine mucosal microbiota induced by a fat-enriched diet reduces the number of IL17-secreting CD4 T cells within the lamina propria of the intestine. This loss of IL17-secreting CD4 T cells is the consequence of an impaired capacity of intestinal antigen presenting cells to activate and trigger the expression of RORgt and the production of IL17 by CD4 T cells. Altogether, an impaired intestinal immune defense, notably the reduced differentiation of RORgt expressing IL17-producing CD4 T cells, favors the onset of a leaky gut leading to the translocation of bacterial factors and live bacteria towards tissues triggering metabolic inflammation; insulin resistance and type 2 diabetes. Hence, the triggering of intestinal defense surrounding RORgt pathway now appears as a potential target mechanism for the control of type 2 diabetes

The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease

SummaryA high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease

Intestinal RORrt-generated Th17 cells control type 2 diabetes: A first antidiabetic target identified from the host to microbiota crosstalk: DOI: 10.14800/ics.1074

The recent discovery of the role played by gut microbiota on the control of metabolic disease opens novel routes for the identification of the causes of type 2 diabetes and obesity. This paradigm could explain the infiltration, by innate and adaptive immune cells, of the adipose tissue, liver, and islets of Langerhans which is responsible for the metabolic inflammation state that leads to impaired insulin action and secretion, and therefore, type 2 diabetes. The identification of the causal role of circulating lipopolysaccharides LPS and peptidoglycans in the development of metabolic inflammation, due to an increased intestinal permeability, led to the leaky gut hypothesis. In addition, whole live bacteria were found in metabolic tissues establishing a tissue microbiota which upon a fat-enriched diet becomes dysbiotic. The process of intestinal bacterial translocation was responsible for the onset of a leaky gut causal to the disease. The translocation of selective sets of intestinal bacteria to the blood could be identified. These blood bacterial 16SrRNA-DNA sequences are considered as biomarkers of the bacterial translocation process. An increased of the corresponding bacterial DNA concentration was predicting the occurrence of type 2 diabetes. Associated to the dysbiotic microbiota translocation, an impaired intestinal immune defense was identified as a cause of the selective leaky gut. The change in small intestine mucosal microbiota induced by a fat-enriched diet reduces the number of IL17-secreting CD4 T cells within the lamina propria of the intestine. This loss of IL17-secreting CD4 T cells is the consequence of an impaired capacity of intestinal antigen presenting cells to activate and trigger the expression of RORgt and the production of IL17 by CD4 T cells. Altogether, an impaired intestinal immune defense, notably the reduced differentiation of RORgt expressing IL17-producing CD4 T cells, favors the onset of a leaky gut leading to the translocation of bacterial factors and live bacteria towards tissues triggering metabolic inflammation; insulin resistance and type 2 diabetes. Hence, the triggering of intestinal defense surrounding RORgt pathway now appears as a potential target mechanism for the control of type 2 diabetes

Effet du 17B-oestradiol sur la réponse T CD4 et l'inflammation (implication dans la physiopathologie de l'encéphalomyélite auto-immune expérimentale)

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

Immuno-microbiota cross and talk: the new paradigm of metabolic diseases.

International audienceOver the last decades the rising occurrence of metabolic diseases throughout the world points to the failure of preventive and therapeutic strategies and of the corresponding molecular and physiological concepts. Therefore, a new paradigm needs to be elucidated. Very recently the intimate cross talk of the intestinal microbiota with the host immune system has opened new avenues. The large diversity of the intestinal microbes' genome, i.e. the metagenome, and the extreme plasticity of the immune system provide a unique balance which, when finely tuned, maintains a steady homeostasis. The discovery that a new microbiota repertoire is one of the causes responsible for the onset of metabolic disease suggests that the relationship with the immune system is impaired. Therefore, we here review the recent arguments that support the view that an alteration in the microbiota to host immune system balance leads to an increased translocation of bacterial antigens towards metabolically active tissues, and could result in a chronic inflammatory state and consequently impaired metabolic functions such as insulin resistance, hepatic fat deposition, insulin unresponsiveness, and excessive adipose tissue development. This imbalance could be at the onset of metabolic disease, and therefore the early treatment of the microbiota dysbiosis or immunomodulatory strategies should prevent and slow down the epidemic of metabolic diseases and hence the corresponding lethal cardiovascular consequences

Therapeutic Memory T Cells Require Costimulation for Effective Clearance of a Persistent Viral Infection ▿

Persistent viral infections are a major health concern worldwide. During persistent infection, overwhelming viral replication and the rapid loss of antiviral T-cell function can prevent immune-mediated clearance of the infection, and therapies to reanimate the immune response and purge persistent viruses have been largely unsuccessful. Adoptive immunotherapy using memory T cells is a highly successful therapeutic approach to eradicate a persistent viral infection. Understanding precisely how therapeutically administered memory T cells achieve clearance should improve our ability to terminate states of viral persistence in humans. Mice persistently infected from birth with lymphocytic choriomeningitis virus are tolerant to the pathogen at the T-cell level and thus provide an excellent model to evaluate immunotherapeutic regimens. Previously, we demonstrated that adoptively transferred memory T cells require recipient dendritic cells to effectively purge an established persistent viral infection. However, the mechanisms that reactivate and sustain memory T-cell responses during clearance of such an infection remain unclear. Here we establish that therapeutic memory T cells require CD80 and CD86 costimulatory signals to efficiently clear an established persistent viral infection in vivo. Early blockade of costimulatory pathways with CTLA-4-Fc decreased the secondary expansion of virus-specific CD8+ and CD4+ memory T cells as well as their ability to produce antiviral cytokines and purge the persistent infection. Late costimulation blockade also reduced virus-specific T-cell numbers, illustrating that sustained interactions with costimulatory molecules is required for efficient T-cell expansion. These findings indicate that antiviral memory T cells require costimulation to efficiently clear a persistent viral infection and that costimulatory pathways can be targeted to modulate the magnitude of an adoptive immunotherapeutic regimen

Estrogen enhances susceptibility to experimental autoimmune myasthenia gravis by promoting type 1-polarized immune responses.

International audienceMyasthenia gravis (MG) is an organ-specific autoimmune disease caused in most cases by autoantibodies against the nicotinic acetylcholine receptor (AChR). It is now well documented that many autoimmune diseases, including MG, are more prevalent in women than in men, and that fluctuations in disease severity occur during pregnancy. These observations raise the question of the potential role of sex hormones, such as estrogens, as mediators of sex differences in autoimmunity. In the present study, we have analyzed the effect of 17beta-estradiol (E2) on the pathogenesis of experimental autoimmune myasthenia gravis (EAMG), an animal model of MG. We show that treatment with E2 before Ag priming is necessary and sufficient to promote AChR-specific Th1 cell expansion in vivo. This time-limited exposure to E2 enhances the production of anti-AChR IgG2a(b) (specific for b allotype; e.g., B6) and IgG2b, but not IgG1, and significantly increases the severity of EAMG in mice. Interestingly, the E2-mediated augmentation in AChR-specific Th1 response correlates with an enhanced production of IL-12 by splenic APCs through the recruitment of CD8alpha(+) dendritic cells. These data provide the first evidence that estrogen enhances EAMG, and sheds some light on the role of sex hormones in immune responses and susceptibility to autoimmune disease in women

Metagenome and metabolism: the tissue microbiota hypothesis.

International audienceOver the last decade, the research community has revealed the role of a new organ: the intestinal microbiota. It is considered as a symbiont that is part of our organism since, at birth, it educates the immune system and contributes to the development of the intestinal vasculature and most probably the nervous system. With the advent of new generation sequencing techniques, a catalogue of genes that belong to this microbiome has been established that lists more than 5 million non-redundant genes called the metagenome. Using germ free mice colonized with the microbiota from different origins, it has been formally demonstrated that the intestinal microbiota causes the onset of metabolic diseases. Further to the role of point mutations in our genome, the microbiota can explain the on-going worldwide pandemic of obesity and diabetes, its dissemination and family inheritance, as well as the diversity of the associated metabolic phenotypes. More recently, the discovery of bacterial DNA within host tissues, such as the liver, the adipose tissue and the blood, which establishes a tissue microbiota, introduces new opportunities to identify targets and predictive biomarkers based on the host to microbiota interaction, as well as to define new strategies for pharmacological, immunomodulatory vaccines and nutritional applications

Estrogen receptor alpha signaling in inflammatory leukocytes is dispensable for 17beta-estradiol-mediated inhibition of experimental autoimmune encephalomyelitis

Estrogen treatment has been shown to exert a protective effect on experimental autoimmune encephalomyelitis (EAE), and is under clinical trial for multiple sclerosis. Although it is commonly assumed that estrogens exert their effect by modulating immune functions, we show in this study that 17beta-estradiol (E2) treatment can inhibit mouse EAE without affecting autoantigen-specific T cell responsiveness and type 1 cytokine production. Using mutant mice in which estrogen receptor alpha (ERalpha) has been unambiguously inactivated, we found that ERalpha was responsible for the E2-mediated inhibition of EAE. We next generated irradiation bone marrow chimeras in which ERalpha expression was selectively impaired in inflammatory T lymphocytes or was limited to the radiosensitive hemopoietic compartment. Our data show that the protective effect of E2 on clinical EAE and CNS inflammation was not dependent on ERalpha signaling in inflammatory T cells. Likewise, EAE development was not prevented by E2 treatment in chimeric mice that selectively expressed ERalpha in the systemic immune compartment. In conclusion, our data demonstrate that the beneficial effect of E2 on this autoimmune disease does not involve ERalpha signaling in blood-derived inflammatory cells, and indicate that ERalpha expressed in other tissues, such as CNS-resident microglia or endothelial cells, mediates this effect