RESUMO
Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic ß cell destruction. Coxsackievirus B3 (CVB3) infection and melanoma differentiation-associated protein 5-dependent (MDA5-dependent) antiviral responses are linked with T1D development. Mutations within IFIH1, coding for MDA5, are correlated with T1D susceptibility, but how these mutations contribute to T1D remains unclear. Utilizing nonobese diabetic (NOD) mice lacking Ifih1 expression (KO) or containing an in-frame deletion within the ATPase site of the helicase 1 domain of MDA5 (ΔHel1), we tested the hypothesis that partial or complete loss-of-function mutations in MDA5 would delay T1D by impairing proinflammatory pancreatic macrophage and T cell responses. Spontaneous T1D developed in female NOD and KO mice similarly, but was significantly delayed in ΔHel1 mice, which may be partly due to a concomitant increase in myeloid-derived suppressor cells. Interestingly, KO male mice had increased spontaneous T1D compared with NOD mice. Whereas NOD and KO mice developed CVB3-accelerated T1D, ΔHel1 mice were protected partly due to decreased type I IFNs, pancreatic infiltrating TNF+ macrophages, IFN-γ+CD4+ T cells, and perforin+CD8+ T cells. Furthermore, ΔHel1 MDA5 protein had reduced ATP hydrolysis compared with wild-type MDA5. Our results suggest that dampened MDA5 function delays T1D, yet loss of MDA5 promotes T1D.
Assuntos
Diabetes Mellitus Tipo 1 , Masculino , Feminino , Camundongos , Animais , Helicase IFIH1 Induzida por Interferon , Camundongos Endogâmicos NOD , Pâncreas/metabolismo , Macrófagos/metabolismoRESUMO
Genome-wide association studies have identified ICOSLG, which encodes the inducible costimulator ligand (ICOSLG or ICOSL) as a susceptibility locus for inflammatory bowel disease. ICOSL has been implicated in the enhancement of pattern recognition receptor signaling in dendritic cells, induction of IL-10 production by CD4 T cells, and the generation of high-affinity antibodies to specific antigens-all of which can potentially explain its involvement in gastrointestinal inflammation. Here, we show that murine ICOSL deficiency results in significant enrichment of IL-10-producing CD4 T cells particularly in the proximal large intestine. Transient depletion of IL-10-producing cells from adult ICOSL-deficient mice induced severe colonic inflammation that was prevented when mice were first treated with metronidazole. ICOSL-deficient mice displayed reduced IgA and IgG antibodies in the colon mucus and impaired serum antibody recognition of microbial antigens, including flagellins derived from mucus-associated bacteria of the Lachnospiraceae family. Confirming the synergy between ICOSL and IL-10, ICOSL deficiency coupled with CD4-specific deletion of the Il10 gene resulted in juvenile onset colitis that was impeded when pups were fostered by ICOSL-sufficient dams. In this setting, we found that both maternally acquired and host-derived antibodies contribute to the life anti-commensal antibody repertoire that mediates this protection in early life. Collectively, our findings reveal a partnership between ICOSL-dependent anti-commensal antibodies and IL-10 in adaptive immune regulation of the microbiota in the large intestine. Furthermore, we identify ICOSL deficiency as an effective platform for exploring the functions of anti-commensal antibodies in host-microbiota mutualism.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Microbioma Gastrointestinal/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Interleucina-10/metabolismo , Animais , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/imunologia , Linfócitos T CD4-Positivos/metabolismo , Colo/imunologia , Colo/microbiologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Ligante Coestimulador de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Knockout , Transdução de Sinais/imunologia , Simbiose/imunologiaRESUMO
Type 1 diabetes (T1D) is a polygenic autoimmune disease characterized by immune-mediated destruction of insulin-producing ß-cells. The concordance rate for T1D in monozygotic twins is ≈30-50%, indicating that environmental factors also play a role in T1D development. Previous studies have demonstrated that enterovirus infections such as coxsackievirus type B (CVB) are associated with triggering T1D. Prior to autoantibody development in T1D, viral RNA and antibodies against CVB can be detected within the blood, stool, and pancreata. An innate pathogen recognition receptor, melanoma differentiation-associated protein 5 (MDA5), which is encoded by the IFIH1 gene, has been associated with T1D onset. It is unclear how single nucleotide polymorphisms in IFIH1 alter the structure and function of MDA5 that may lead to exacerbated antiviral responses contributing to increased T1D-susceptibility. Binding of viral dsRNA via MDA5 induces synthesis of antiviral proteins such as interferon-alpha and -beta (IFN-α/ß). Viral infection and subsequent IFN-α/ß synthesis can lead to ER stress within insulin-producing ß-cells causing neo-epitope generation, activation of ß-cell-specific autoreactive T cells, and ß-cell destruction. Therefore, an interplay between genetics, enteroviral infections, and antiviral responses may be critical for T1D development.
RESUMO
Targeting retinoid X receptor (RXR) has been proposed as one of the therapeutic strategies to treat individuals with metabolic syndrome, as RXR heterodimerizes with multiple nuclear receptors that regulate genes involved in metabolism. Despite numerous efforts, RXR ligands (rexinoids) have not been approved for clinical trials to treat metabolic syndrome due to the serious side effects such as hypertriglyceridemia and altered thyroid hormone axis. In this study, we demonstrate a novel rexinoid-like small molecule, UAB126, which has positive effects on metabolic syndrome without the known side effects of potent rexinoids. Oral administration of UAB126 ameliorated obesity, insulin resistance, hepatic steatosis, and hyperlipidemia without changes in food intake, physical activity, and thyroid hormone levels. RNA-sequencing analysis revealed that UAB126 regulates the expression of genes in the liver that are modulated by several nuclear receptors, including peroxisome proliferator-activated receptor α and/or liver X receptor in conjunction with RXR. Furthermore, UAB126 not only prevented but also reversed obesity-associated metabolic disorders. The results suggest that optimized modulation of RXR may be a promising strategy to treat metabolic disorders without side effects. Thus, the current study reveals that UAB126 could be an attractive therapy to treat individuals with obesity and its comorbidities.
Assuntos
Dieta Hiperlipídica , Fígado Gorduroso/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptores X de Retinoides/agonistas , Animais , Fígado Gorduroso/sangue , Hiperlipidemias/sangue , Lipídeos/sangue , Masculino , Camundongos , Obesidade/sangueRESUMO
T cell receptor (TCR) affinity is a critical factor of Treg lineage commitment, but whether self-reactivity is a determining factor in peripheral Treg function remains unknown. Here, we report that a high degree of self-reactivity is crucial for tissue-specific Treg function in autoimmunity. Based on high expression of CD5, we identified a subset of self-reactive Tregs expressing elevated levels of T-bet, GITR, CTLA-4, and ICOS, which imparted significant protection from autoimmune diabetes. We observed that T-bet expression in Tregs, necessary for control of Th1 autoimmunity, could be induced in an IFNγ-independent fashion and, unlike in conventional T cells (Tconv), was strongly correlated with the strength of TCR signaling. The level of CD5 similarly identified human Tregs with an increased functional profile, suggesting that CD5hi Tregs may constitute an efficacious subpopulation appropriate for use in adoptive Treg therapies for treatment of inflammatory conditions. Overall, this work establishes an instrumental role of high TCR self-reactivity in driving Treg function.
Assuntos
Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Adulto , Animais , Antígenos CD5 , Células Cultivadas , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/terapia , Modelos Animais de Doenças , Feminino , Voluntários Saudáveis , Humanos , Imunoterapia Adotiva/métodos , Ilhotas Pancreáticas , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas com Domínio T/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante , Adulto JovemRESUMO
Regulatory T cells (Tregs) use a distinct TCR repertoire and are more self-reactive compared with conventional T cells. However, the extent to which TCR affinity regulates the function of self-reactive Tregs is largely unknown. In this study, we used a two-TCR model to assess the role of TCR affinity in Treg function during autoimmunity. We observed that high- and low-affinity Tregs were recruited to the pancreas and contributed to protection from autoimmune diabetes. Interestingly, high-affinity cells preferentially upregulated the TCR-dependent Treg functional mediators IL-10, TIGIT, GITR, and CTLA4, whereas low-affinity cells displayed increased transcripts for Areg and Ebi3, suggesting distinct functional profiles. The results of this study suggest mechanistically distinct and potentially nonredundant roles for high- and low-affinity Tregs in controlling autoimmunity.