Effect of the sodium-glucose cotransporter-2 inhibitor, DWP16001, as an add-on therapy to insulin for diabetic dogs: A pilot study.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of anti-hyperglycaemic agents. OBJECTIVE: This study aimed to evaluate the safety and the adjuvant glycaemic control effect of an SGLT2 inhibitor, DWP16001, in diabetic dogs receiving insulin treatment. METHODS: Nineteen diabetic dogs receiving insulin treatment (NPH, porcine lente and glargine insulin) were divided into two groups according to dosing frequency: DWP TOD group (n = 10) and DWP SID group (n = 9). In the DWP TOD group, 0.025 mg/kg of DWP16001 was administered once every 3 days, whereas, in the DWP SID group, 0.025 mg/kg of DWP16001 was administered once a day. Food intake was maintained during the trial period. Hypoglycaemia, ketoacidosis or unexpected life-threatening reactions were assessed as adverse effects before and after DWP16001 administration. We compared insulin requirement reduction and blood glucose level control between two groups. RESULTS: No specific adverse effects were observed during the clinical trial, and haematological parameter remained unchanged. Moreover, the fasting glucose levels and daily insulin dose in the DWP TOD group were lower than the pre-administration values, but not significantly different for 8 weeks. Systolic blood pressure, fructosamine and insulin dose decreased significantly in the DWP SID group compared to the DWP TOD group at 8 weeks (p < 0.05) without affecting food consumption. Among these patients, 10 patients were monitored while receiving DWP16001 for 12 months (DWP TOD group n = 5, DWP SID group n = 5). The fasting glucose and fructosamine levels and daily insulin dose were reduced in both groups at 12 months compared with those before receiving DWP16001. CONCLUSION: When DWP16001, an SGLT2 inhibitor, was supplied to dogs with type 1 diabetes, no adverse effects were observed, and it was confirmed that the administered insulin dose can be reduced in controlling blood glucose.

DWN12088, A Prolyl-tRNA Synthetase Inhibitor, Alleviates Hepatic Injury in Nonalcoholic Steatohepatitis.

BACKGRUOUND: Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression. METHODS: Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture. RESULTS: DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor ß (TGFß)-induced pro-fibrotic gene expression by suppressing TGFß receptor 1 (TGFßR1)/Smad2/3 and TGFßR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis. CONCLUSION: Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade.

The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function. SIGNIFICANCE: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti-PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell-mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489.

Metabolic modulation of mitochondrial mass during CD4+ T cell activation.

Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.

Microbiota-dependent regulation of costimulatory and coinhibitory pathways via innate immune sensors and implications for immunotherapy.

Our bodies are inhabited by trillions of microorganisms. The host immune system constantly interacts with the microbiota in barrier organs, including the intestines. Over decades, numerous studies have shown that our mucosal immune system is dynamically shaped by a variety of microbiota-derived signals. Elucidating the mediators of these interactions is an important step for understanding how the microbiota is linked to mucosal immune homeostasis and gut-associated diseases. Interestingly, the efficacy of cancer immunotherapies that manipulate costimulatory and coinhibitory pathways has been correlated with the gut microbiota. Moreover, adverse effects of these therapies in the gut are linked to dysregulation of the intestinal immune system. These findings suggest that costimulatory pathways in the immune system might serve as a bridge between the host immune system and the gut microbiota. Here, we review mechanisms by which commensal microorganisms signal immune cells and their potential impact on costimulation. We highlight how costimulatory pathways modulate the mucosal immune system through not only classical antigen-presenting cells but also innate lymphocytes, which are highly enriched in barrier organs. Finally, we discuss the adverse effects of immune checkpoint inhibitors in the gut and the possible relationship with the gut microbiota.

Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.

The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2-RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2-RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2-RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.

Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1.

Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.

SGLT2 inhibition ameliorates nano plastics-induced premature endothelial senescence and dysfunction.

Nano plastics (NPs) have been a significant threat to human health and are known to cause premature endothelial senescence. Endothelial senescence is considered one of the primary risk factors contributing to numerous cardiovascular disorders. Recent studies have suggested that inhibition of sodium glucose co-transporter (SGLT2) ameliorates endothelial senescence and dysfunction. Therefore, our study intends to explore the role of SGLT2 in NPs-induced endothelial senescence and dysfunction. Porcine coronary artery and its endothelial cells were treated with NPs in the presence or absence of Enavogliflozin (ENA), a SGLT2 inhibitor and then SGLTs expression, senescence markers and vascular function were evaluated. NPs significantly up-regulated SGLT2 and ENA significantly decreased NPs-induced senescence-associated-ß-gal activity, cell-cycle arrest, and senescence markers p53 and p21 suggesting that inhibition of SGLT2 prevents NPs-induced endothelial senescence. In addition, ENA decreased the formation of reactive oxygen species with the downregulation of Nox2, and p22phox. Furthermore, SGLT2 inhibition also up regulated the endothelial nitric oxide synthase expression along with improving vascular function. In conclusion, premature endothelial senescence by NPs is, at least in part, associated with SGLT2 and it could be a potential therapeutic target for preventing and/or treating environmental pollutants-induced cardiovascular disorders mediated by endothelial senescence and dysfunction.

Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis.

The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is ∼4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.

Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans.

Enavogliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor approved for clinical use in South Korea. As SGLT2 inhibitors are a treatment option for patients with diabetes, enavogliflozin is expected to be prescribed in various populations. Physiologically based pharmacokinetic (PBPK) modelling can rationally predict the concentration-time profiles under altered physiological conditions. In previous studies, one of the metabolites (M1) appeared to have a metabolic ratio between 0.20 and 0.25. In this study, PBPK models for enavogliflozin and M1 were developed using published clinical trial data. The PBPK model for enavogliflozin incorporated a non-linear urinary excretion in a mechanistically arranged kidney model and a non-linear formation of M1 in the liver. The PBPK model was evaluated, and the simulated pharmacokinetic characteristics were in a two-fold range from those of the observations. The pharmacokinetic parameters of enavogliflozin were predicted using the PBPK model under pathophysiological conditions. PBPK models for enavogliflozin and M1 were developed and validated, and they seemed useful for logical prediction.

Lateral hypothalamic leptin receptor neurons drive hunger-gated food-seeking and consummatory behaviours in male mice.

For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LHLepR neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LHLepR neurons promotes seeking or consummatory behaviours and inhibition of LHLepR neurons reduces consummatory behaviours. The activity of LHLepR neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours.

Tailored Self-Assembled Monolayer using Chemical Coupling for Indium-Gallium-Zinc Oxide Thin-Film Transistors: Multifunctional Copper Diffusion Barrier.

Controlling the contact properties of a copper (Cu) electrode is an important process for improving the performance of an amorphous indium-gallium-zinc oxide (a-IGZO) thin-film transistor (TFT) for high-speed applications, owing to the low resistance-capacitance product constant of Cu. One of the many challenges in Cu application to a-IGZO is inhibiting high diffusivity, which causes degradation in the performance of a-IGZO TFT by forming electron trap states. A self-assembled monolayer (SAM) can perfectly act as a Cu diffusion barrier (DB) and passivation layer that prevents moisture and oxygen, which can deteriorate the TFT on-off performance. However, traditional SAM materials have high contact resistance and low mechanical-adhesion properties. In this study, we demonstrate that tailoring the SAM using the chemical coupling method can enhance the electrical and mechanical properties of a-IGZO TFTs. The doping effects from the dipole moment of the tailored SAMs enhance the electrical properties of a-IGZO TFTs, resulting in a field-effect mobility of 13.87 cm2/V·s, an on-off ratio above 107, and a low contact resistance of 612 Ω. Because of the high electrical performance of tailored SAMs, they function as a Cu DB and a passivation layer. Moreover, a selectively tailored functional group can improve the adhesion properties between Cu and a-IGZO. These multifunctionally tailored SAMs can be a promising candidate for a very thin Cu DB in future electronic technology.

Evaluation of safety and anti-obesity effects of DWP16001 in naturally obese dogs.

BACKGROUND: The aim of this study was to investigate the anti-obesity effects of DWP16001, a sodium-glucose cotransporter-2 (SGLT2 inhibitor), in naturally obese dogs. A total of 20 dogs were divided into four equal groups: one obese control (OC group), and three treated groups; DWP0.2 group, DWP0.5 group, and DWP1 group. OC group fed with food for maintenance and treated groups were fed with food for maintenance with 0.2 mg/kg DWP16001, 0.5 mg/kg DWP16001 and 1 mg/kg DWP16001, respectively. The food for maintenance was provided to dogs as 2 RER (Resting energy requirement) in kcal and DWP16001-supplemented food was administered once a day for 8 weeks. RESULTS: Body condition score, body weight, and fat thickness were significantly reduced (P < 0.05) in the DWP0.2 group compared with the OC group, respectively without affecting the food consumption. At the 10th week the food consumption rate was 101.35 ± 2.56, 166.59 ± 4.72, 98.47 ± 1.44 and 123.15 ± 2.45% compared with initial food consumption rate. Body fat percentage, chest and waist circumference, blood glucose, and insulin were reduced compared to OC group but not significantly different from those of the OC group during experimental period. Serum alanine aminotransferase, alkaline phosphatase, creatine phosphokinase, and creatinine were significantly reduced in DWP0.2 group on 8 weeks. Serum cholesterol and triglycerides were reduced but not significantly. No specific adverse effects were observed throughout the experiment, and hematological parameters were unchanged. The results indicate that DWP16001 was not harmful to the dogs in our study and might have anti-obesity effects in naturally obese dogs. CONCLUSIONS: The above results and discussion suggest that DWP16001 is safe and might have anti-obesity effects in naturally obese dogs.

Clinical effectiveness of liraglutide on weight loss in South Koreans: First real-world retrospective data on Saxenda in Asia.

ABSTRACT: Among Asian countries, South Korea was the first to approve liraglutide as a treatment for obesity. Thus, the clinical effectiveness of liraglutide has not been studied in Asian populations.In this study, we retrospectively analyzed obese patients [body mass index (BMI) >27 kg/m2] who were treated with liraglutide between March 2018 and March 2019 in a single clinic. Weight, BMI, HbA1c, and clinical data were collected before liraglutide treatment. Changes in body weight and composition and their relationships with clinical variables were examined at re-prescription dates within 30, 60, 90, and 180 days.A total of 169 subjects were studied. The average age was 41.5 years, and 42% of the subjects were male. The average weight was 85.2 kg, and the average BMI was 30.8 kg/m2. Weight reduction was significant (-5.5 ±â€Š3.4 kg, 30 days: -3.2 ±â€Š1.8 kg, 60 days: -4.5 ±â€Š2.3 kg, 90 days: -6.3 ±â€Š2.6 kg, 180 days: -7.8 ±â€Š3.5 kg) during the follow-up period and increased with longer treatment time (P < .001). The percentages of subjects that showed ≥ 5% and ≥ 10% body weight reduction were 62.1% and 17.2%, respectively. In the body composition analysis, skeletal muscle weight loss was -3.56 ±â€Š29.7%, which was significantly smaller than fat weight loss of -11.06 ±â€Š10.4% (P = .03). Weight loss was not significantly related to age, sex, baseline BMI, baseline HbA1c, smoking status, alcohol consumption, coffee intake.In conclusion, Liraglutide treatment led to meaningful weight loss in South Korean patients, and fat mass reduction was prominent during treatment. Furthermore, liraglutide showed greater clinical effectiveness with longer treatment time.

The Selenoprotein MsrB1 Instructs Dendritic Cells to Induce T-Helper 1 Immune Responses.

Immune activation associates with the intracellular generation of reactive oxygen species(ROS). To elicit effective immune responses, ROS levels must be balanced. Emerging evidenceshows that ROS-mediated signal transduction can be regulated by selenoproteins such asmethionine sulfoxide reductase B1 (MsrB1). However, how the selenoprotein shapes immunityremains poorly understood. Here, we demonstrated that MsrB1 plays a crucial role in the ability ofdendritic cells (DCs) to provide the antigen presentation and costimulation that are needed forcluster of differentiation antigen four (CD4) T-cell priming in mice. We found that MsrB1 regulatedsignal transducer and activator of transcription-6 (STAT6) phosphorylation in DCs. Moreover, bothin vitro and in vivo, MsrB1 potentiated the lipopolysaccharide (LPS)-induced Interleukin-12 (IL-12)production by DCs and drove T-helper 1 (Th1) differentiation after immunization. We propose thatMsrB1 activates the STAT6 pathway in DCs, thereby inducing the DC maturation and IL-12production that promotes Th1 differentiation. Additionally, we showed that MsrB1 promotedfollicular helper T-cell (Tfh) differentiation when mice were immunized with sheep red blood cells.This study unveils as yet unappreciated roles of the MsrB1 selenoprotein in the innate control ofadaptive immunity. Targeting MsrB1 may have therapeutic potential in terms of controllingimmune reactions.

Food Craving, Seeking, and Consumption Behaviors: Conceptual Phases and Assessment Methods Used in Animal and Human Studies.

What drives us to eat? It is one of the most fundamental questions in the obesity research field which have been investigated for centuries. Numerous novel in vivo technologies in the neuroscience field allows us to reevaluate the multiple components and phases of food-related behaviors. Focused on the cognitive, executive, behavioral and temporal aspects, food-related behaviors can be distinguished into appetitive phase (food craving→food seeking) and consummatory phase (food consumption). Food craving phase is an internal state or stage in which the animal has the motivation to eat the food but there is no actual food specific behaviors or actions. Food seeking phase entails repeated behaviors with a food searching purpose until the animal discovers the food (or food-related cue) and the approach behavior stage after the discovery of food. Food consumption phase is the step that the animal grabs, chews and intake the food. This review will specifically focus on characteristics and evaluation methods for each phase of food-related behavior in rodent, non-human primates and human.

Lipid-Reactive T Cells in Immunological Disorders of the Lung.

Regulation of T cell-mediated immunity in the lungs is critical for prevention of immune-related lung disorders and for host protection from pathogens. While the prevalent view of pulmonary T cell responses is based on peptide recognition by antigen receptors, called T cell receptors (TCR), on the T cell surface in the context of classical major histocompatibility complex (MHC) molecules, novel pathways involving the presentation of lipid antigens by cluster of differentiation 1 (CD1) molecules to lipid-reactive T cells are emerging as key players in pulmonary immune system. Whereas, genetic conservation of group II CD1 (CD1d) in mouse and human genomes facilitated numerous in vivo studies of CD1d-restricted invariant natural killer T (iNKT) cells in lung diseases, the recent development of human CD1-transgenic mice has made it possible to examine the physiological roles of group I CD1 (CD1a-c) molecules in lung immunity. Here, we discuss current understanding of the biology of CD1-reactive T cells with a specific focus on their roles in several pulmonary disorders.

Role of non-classical T cells in skin immunity.

The immune network controls homeostasis and inflammation of the skin. Immune cells use their antigen receptors to respond to a wide range of insults originating from microbes and allergens. T cells, which are key effector cells in the immune system, engage their T cell receptors (TCRs) to recognize self and foreign antigens in the context of classical major histocompatibility complex (MHC) molecules, MHC-like CD1 proteins, or MHC class I-related molecules. Recently, increasing evidence has demonstrated that T cells activated by non-canonical antigens are important in skin diseases. This review focuses on recent studies examining the roles of non-classical antigen-presenting molecules and their reactive T cells in the skin immune system. Additionally, we describe the types of ligands that activate these unconventional T cells through the non-classical MHC pathway. Finally, we highlight recent advances in the understanding of the physiological functions of non-classical T cells in the skin. Further investigation may result in the development of new therapeutic strategies for treating immune-related skin diseases.

Signaling function of PRC2 is essential for TCR-driven T cell responses.

Differentiation and activation of T cells require the activity of numerous histone lysine methyltransferases (HMT) that control the transcriptional T cell output. One of the most potent regulators of T cell differentiation is the HMT Ezh2. Ezh2 is a key enzymatic component of polycomb repressive complex 2 (PRC2), which silences gene expression by histone H3 di/tri-methylation at lysine 27. Surprisingly, in many cell types, including T cells, Ezh2 is localized in both the nucleus and the cytosol. Here we show the presence of a nuclear-like PRC2 complex in T cell cytosol and demonstrate a role of cytosolic PRC2 in T cell antigen receptor (TCR)-mediated signaling. We show that short-term suppression of PRC2 precludes TCR-driven T cell activation in vitro. We also demonstrate that pharmacological inhibition of PRC2 in vivo greatly attenuates the severe T cell-driven autoimmunity caused by regulatory T cell depletion. Our data reveal cytoplasmic PRC2 is one of the most potent regulators of T cell activation and point toward the therapeutic potential of PRC2 inhibitors for the treatment of T cell-driven autoimmune diseases.