Interleukin-17 directly stimulates tumor infiltrating Tregs to prevent cancer development
BackgroundInterleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance,but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses.MethodsWe generated a conditional knockout of Il17ra in Tregs by crossing Foxp3-YFP-Cre mice to Il17ra-flox mice (Il17ra ΔTreg mice). Subsequently,we adoptively transferred bone marrow cells from Il17ra ΔTreg mice to a mouse model of sporadic colorectal cancer (Cdx2-Cre +/Apc F/+),to selectively ablate IL-17 direct signaling on Tregs in colorectal cancer. Single cell RNA sequencing and bulk RNA sequencing were performed on purified Tregs from mouse colorectal tumors,and compared to those of human tumor infiltrating Treg cells.ResultsIL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors. Ablation of IL-17RA,specifically in Tregs,resulted in increased Th17 cells,and exacerbated tumor development. Mechanistically,tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation,maturation,and suppression function,and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming,we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing,and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function.ConclusionIL-17 directly signals to Tregs and promotes their maturation and function. This signaling pathway constitutes a negative feedback loop that controls cancer-promoting inflammation in CRC.
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产品号#：
19765
19765RF
19858
19858RF
产品名：
EasySep™小鼠Naïve CD4+ T细胞分选试剂盒
RoboSep™ 小鼠Naïve CD4+ T细胞分选试剂盒
EasySep™小鼠Naïve CD8+ T细胞分选试剂盒
RoboSep™ 小鼠Naïve CD8+ T细胞分选试剂盒
(May 2024)
iScience 27 6
Moderate-intensity aerobic exercise training improves CD8
SummaryAerobic exercise training (AET) has emerged as a strategy to reduce cancer mortality,however,the mechanisms explaining AET on tumor development remain unclear. Tumors escape immune detection by generating immunosuppressive microenvironments and impaired T cell function,which is associated with T cell mitochondrial loss. AET improves mitochondrial content and function,thus we tested whether AET would modulate mitochondrial metabolism in tumor-infiltrating lymphocytes (TIL). Balb/c mice were subjected to a treadmill AET protocol prior to CT26 colon carcinoma cells injection and until tumor harvest. Tissue hypoxia,TIL infiltration and effector function,and mitochondrial content,morphology and function were evaluated. AET reduced tumor growth,improved survival,and decreased tumor hypoxia. An increased CD8+ TIL infiltration,IFN-γ and ATP production promoted by AET was correlated with reduced mitochondrial loss in these cells. Collectively,AET decreases tumor growth partially by increasing CD8+ TIL effector function through an improvement in their mitochondrial content and function. Graphical abstract Highlights•Exercise training reduces tumor growth and improves survival in colorectal cancer•Trained mice present tumors with less hypoxia and higher CD8+ T cells infiltration•The production of IFNγ by CD8+ TIL is increased in exercise-trained mice•CD8+ TIL from trained mice show higher mitochondrial density and function Natural sciences; Biological sciences; Biochemistry; Physiology; Immunology; Systems biology; Cancer systems biology
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产品号#：
18953
18953RF
17666
17666RF
17696
17696RF
18756
18756RF
18945
18957
18957RF
产品名：
EasySep™小鼠CD8a正选试剂盒II
RoboSep™ 小鼠CD8a正选试剂盒II
EasySep™小鼠PE正选试剂盒II
RoboSep™ 小鼠PE正选试剂盒II
EasySep™小鼠PE正选试剂盒II
RoboSep™ 小鼠PE正选试剂盒II
EasySep™小鼠SCA1正选试剂盒
RoboSep™ 小鼠SCA1正选试剂盒含滤芯吸头
EasySep™ 小鼠CD45正选试剂盒
EasySep™小鼠CD138正选试剂盒
RoboSep™ 小鼠CD138正选试剂盒
(May 2024)
Molecular cell 84 11
Pathways for macrophage uptake of cell-free circular RNAs
SUMMARY Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA,which may comprise cellular debris and pathogen genomes. Here we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid,energy-dependent,and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake,with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1,toll-like receptors,and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs,a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an “eat me” signal and danger-associated molecular pattern,indicating orderly pathways of recognition and disposal. eTOC Blurb: Amaya et. al. explores how cells take up extracellular circular RNAs (CircRNAs) and their impact on immune signaling. Macrophages readily internalize circRNAs,and this study identifies the specific receptors and signaling pathways governing circRNA internalization,highlighting their role as signaling molecules for immune recognition and disposal. Graphical Abstract
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产品号#：
19058
19058RF
100-1525
19059
19059RF
07811
07861
18060
18061
产品名：
EasySep™人单核细胞富集试剂盒（不去除CD16）
RoboSep™ 人单核细胞富集试剂盒（不去除CD16）含滤芯吸头
EasySep™人单核细胞富集试剂盒（不去除CD16）
EasySep™人单核细胞富集试剂盒
RoboSep™ 人单核细胞富集试剂盒含滤芯吸头
Lymphoprep™
Lymphoprep™
Lymphoprep™
Lymphoprep™
(Jun 2024)
Cell Reports Medicine 5 6
A CD36-dependent non-canonical lipid metabolism program promotes immune escape and resistance to hypomethylating agent therapy in AML
SummaryEnvironmental lipids are essential for fueling tumor energetics,but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here,we find that CD36,a transporter for exogenous lipids,promotes acute myeloid leukemia (AML) immune evasion. We show that,separately from its established role in lipid oxidation,CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway,and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently,NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably,high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling,leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression. Graphical abstract Highlights•CD36 on AML cells suppresses T cell proliferation independently of lipid oxidation•OxLDL and palmitate synergize to inhibit T cell activity via CD36 signaling in AML cells•Targeting CD36 signaling with statins improves the efficacy of decitabine therapy in AML Guo et al. find that OxLDL and palmitate uptake by AML cells synergistically upregulates CD36-mediated innate immune signaling to suppress T cell activity. High-fat-diet or decitabine treatment dampened the therapeutic effect by hijacking CD36 signaling. Targeting the CD36 immunosuppressive pathway with statins improves the efficacy of decitabine therapy in AML.
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产品号#：
09600
09605
09650
09655
17897
17897RF
产品名：
StemSpan™ SFEM
StemSpan™ SFEM II
StemSpan™ SFEM
StemSpan™ SFEM II
EasySep™人脐带血CD34正选试剂盒III
RoboSep™ 人脐带血CD34正选试剂盒III
(Jun 2024)
bioRxiv 37
NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion
The progressive decline of CD8 T cell effector function—also known as terminal exhaustion—is a major contributor to immune evasion in cancer. Yet,the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here,we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis,which mediates cellular adaptations to oxidative stress,directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically,we identify PTGIR,a receptor for the circulating eicosanoid prostacyclin,as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover,lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together,these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states. One Sentence Summary:The KEAP1-NRF2 pathway is hyperactivated in terminally exhausted CD8 T cells and drives T cell dysfunction via transcriptional regulation of the prostacyclin receptor,Ptgir.
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产品号#：
19853
19853RF
17667
17667RF
产品名：
EasySep™小鼠CD8+ T细胞分选试剂盒
RoboSep™ 小鼠CD8+ T细胞分选试剂盒
EasySep™小鼠APC正选试剂盒II
RoboSep™ 小鼠APC正选试剂盒II
(Jul 2024)
Nature Communications 15
Tumor cell-directed STING agonist antibody-drug conjugates induce type III interferons and anti-tumor innate immune responses
Activating interferon responses with STING agonists (STINGa) is a current cancer immunotherapy strategy,and therapeutic modalities that enable tumor-targeted delivery via systemic administration could be beneficial. Here we demonstrate that tumor cell-directed STING agonist antibody-drug-conjugates (STINGa ADCs) activate STING in tumor cells and myeloid cells and induce anti-tumor innate immune responses in in vitro,in vivo (in female mice),and ex vivo tumor models. We show that the tumor cell-directed STINGa ADCs are internalized into myeloid cells by Fcγ-receptor-I in a tumor antigen-dependent manner. Systemic administration of STINGa ADCs in mice leads to STING activation in tumors,with increased anti-tumor activity and reduced serum cytokine elevations compared to a free STING agonist. Furthermore,STINGa ADCs induce type III interferons,which contribute to the anti-tumor activity by upregulating type I interferon and other key chemokines/cytokines. These findings reveal an important role for type III interferons in the anti-tumor activity elicited by STING agonism and provide rationale for the clinical development of tumor cell-directed STINGa ADCs. Activation of the STING pathway can promote anti-tumor immunity. Here the authors generate tumor cell-directed STING agonist antibody-drug conjugates that activate STING in tumor and myeloid cells,promoting anti-tumor innate immune responses in preclinical cancer models.
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产品号#：
17858
17858RF
100-0694
07800
07850
100-0697
17698
17698RF
19359
19359RF
产品名：
EasySep™人CD14正选试剂盒II
RoboSep™ 人CD14正选试剂盒II
EasySep™人CD14正选试剂盒II
氯化铵溶液
氯化铵溶液
EasySep™人单核细胞分选试剂盒
EasySep™ “Do-It-Yourself”正选试剂盒II
RoboSep™ “Do-It-Yourself”正选试剂盒II
EasySep™人单核细胞分选试剂盒
RoboSep™ 人单核细胞分选试剂盒
(May 2024)
iScience 27 7
Metabolic reprogramming and dysregulated IL-17 production impairs CD4 T cell function post sepsis
SummarySepsis survivors are at high risk for infection-related rehospitalization and mortality for years following the resolution of the acute septic event. These infection-causing microorganisms generally do not cause disease in immunocompetent hosts,suggesting that the post-septic immune response is compromised. Given the importance of CD4 T cells in the development of long-lasting protective immunity,we analyzed their post-septic function. Here we showed that sepsis induced chronic increased and non-specific production of IL-17 by CD4 T cells,resulting in the inability to mount an effective immune response to a secondary pneumonia challenge. Altered cell function was associated with metabolic reprogramming,characterized by mitochondrial dysfunction and increased glycolysis. This metabolic reprogramming began during the acute septic event and persisted long after sepsis had resolved. Our findings reveal cell metabolism as a potential therapeutic target. Given the critical role of cell metabolism in the physiological and pathophysiological processes of immune cells,these findings reveal a potential new therapeutic target to help mitigate sepsis survivors’ susceptibility to secondary infections. Graphical abstract Highlights•Sepsis survivors demonstrate dysfunctional CD4 T cell immunity•Sepsis induces persistent mitochondrial dysfunction in CD4 T cells•Post-septic CD4 T cells are highly glycolytic and exhibit a Th17 phenotype•Sepsis impairs the CD4 T cell recall response Physiology; Molecular biology; Immunology; Components of the immune system
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产品号#：
19852
19852RF
17899
19853
19853RF
产品名：
EasySep™小鼠CD4+ T细胞分选试剂盒
RoboSep™ 小鼠CD4+ T细胞分选试剂盒
EasySep™ 死细胞去除 (Annexin V) 试剂盒
EasySep™小鼠CD8+ T细胞分选试剂盒
RoboSep™ 小鼠CD8+ T细胞分选试剂盒
(Jul 2024)
Nature Cell Biology 26 7
Neutrophil-derived migrasomes are an essential part of the coagulation system
Migrasomes are organelles that are generated by migrating cells. Here we report the key role of neutrophil-derived migrasomes in haemostasis. We found that a large number of neutrophil-derived migrasomes exist in the blood of mice and humans. Compared with neutrophil cell bodies and platelets,these migrasomes adsorb and enrich coagulation factors on the surface. Moreover,they are highly enriched with adhesion molecules,which enable them to preferentially accumulate at sites of injury,where they trigger platelet activation and clot formation. Depletion of neutrophils,or genetic reduction of the number of these migrasomes,significantly decreases platelet plug formation and impairs coagulation. These defects can be rescued by intravenous injection of purified neutrophil-derived migrasomes. Our study reveals neutrophil-derived migrasomes as a previously unrecognized essential component of the haemostasis system,which may shed light on the cause of various coagulation disorders and open therapeutic possibilities. Jiang et al. document an abundance of neutrophil-derived migrasomes in the blood of mice and humans and show that migrasomes are enriched in coagulation factors,accumulate at sites of injury and trigger platelet activation and clot formation.
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产品号#：
17957
19762
19762RF
17957RF
产品名：
EasySep™人中性粒细胞分选试剂盒
EasySep™小鼠中性粒细胞富集试剂盒
RoboSep™ 小鼠中性粒细胞富集试剂盒含滤芯吸头
RoboSep™ 人中性粒细胞分选试剂盒
(Jul 2024)
Frontiers in Pharmacology 15 1
Pharmacologic inhibition of dipeptidyl peptidase 1 (cathepsin C) does not block
Recently developed small-molecule inhibitors of the lysosomal protease dipeptidyl peptidase 1 (DPP1),also known as cathepsin C (CatC),can suppress suppurative inflammation in vivo by blocking the processing of zymogenic (pro-) forms of neutrophil serine proteases (NSPs),including neutrophil elastase,proteinase 3,and cathepsin G. DPP1 also plays an important role in activating granzyme serine proteases that are expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Therefore,it is critical to determine whether DPP1 inhibition can also cause off-target suppression of CTL/NK-cell-mediated killing of virus-infected or malignant cells. Herein,we demonstrate that the processing of human granzymes A and B,transitioning from zymogen to active proteases,is not solely dependent on DPP1. Thus,the killing of target cells by primary human CD8+ T cells,NK cells,and gene-engineered anti-CD19 CAR T cells was not blocked in vitro even after prior exposure to high concentrations of the reversible DPP1 inhibitor brensocatib. Consistent with this observation,the turnover of model granzyme A/B peptide substrates in the human CTL/NK cell lysates was not significantly reduced by brensocatib. In contrast,preincubation with brensocatib almost entirely abolished (>90%) both the cytotoxic activity of mouse CD8+ T cells and granzyme substrate turnover. Overall,our finding that the effects of DPP1 inhibition on human cytotoxic lymphocytes are attenuated in comparison to those of mice indicates that granzyme processing/activation pathways differ between mice and humans. Moreover,the in vitro data suggest that human subjects treated with reversible DPP1 inhibitors,such as brensocatib,are unlikely to experience any appreciable deficits in CTL/NK-cell-mediated immunities.
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产品号#：
100-0785
10970
10990
17951
100-0695
17951RF
产品名：
ImmunoCult™ 人CD3/CD28/CD2 T细胞激活剂
ImmunoCult™ 人CD3/CD28/CD2 T细胞激活剂
ImmunoCult™ 人CD3/CD28/CD2 T细胞激活剂
EasySep™人T细胞分选试剂盒
EasySep™人T细胞分选试剂盒
RoboSep™ 人T细胞分选试剂盒
(Jul 2024)
Scientific Reports 14
Identification of organs of origin of macrophages that produce presepsin via neutrophil extracellular trap phagocytosis
Presepsin (P-SEP) is a specific biomarker for sepsis. Monocytes produce P-SEP by phagocytosing neutrophil extracellular traps (NETs). Herein,we investigated whether M1 macrophages (M1 MΦs) are the primary producers of P-SEP after NET phagocytosis. We co-cultured M1 MΦs and NETs from healthy participants,measured P-SEP levels in the culture medium supernatant,and detected P-SEP using western blotting. When NETs were co-cultured with M1 MΦs,the P-SEP level of the culture supernatant was high. Notably,we demonstrated,for the first time,the intracellular kinetics of P-SEP production by M1 MΦs via NET phagocytosis: M1 MΦs produced P-SEP intracellularly 15 min after NET phagocytosis and then released it extracellularly. In a sepsis mouse model,the blood NET ratio and P-SEP levels,detected using ELISA,were significantly increased (p < 0.0001). Intracellular P-SEP analysis via flow cytometry demonstrated that lung,liver,and kidney MΦs produced large amounts of P-SEP. Therefore,we identified these organs as the origin of M1 MΦs that produce P-SEP during sepsis. Our data indicate that the P-SEP level reflects the trend of NETs,suggesting that monitoring P-SEP can be used to both assess NET-induced organ damage in the lungs,liver,and kidneys during sepsis and determine treatment efficacy.
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产品号#：
19359
100-0697
19359RF
产品名：
EasySep™人单核细胞分选试剂盒
EasySep™人单核细胞分选试剂盒
RoboSep™ 人单核细胞分选试剂盒
(Jul 2024)
Frontiers in Immunology 15
Single cell multi-omic analysis identifies key genes differentially expressed in innate lymphoid cells from COVID-19 patients
IntroductionInnate lymphoid cells (ILCs) are enriched at mucosal surfaces where they respond rapidly to environmental stimuli and contribute to both tissue inflammation and healing. MethodsTo gain insight into the role of ILCs in the pathology and recovery from COVID-19 infection,we employed a multi-omics approach consisting of Abseq and targeted mRNA sequencing to respectively probe the surface marker expression,transcriptional profile and heterogeneity of ILCs in peripheral blood of patients with COVID-19 compared with healthy controls. ResultsWe found that the frequency of ILC1 and ILC2 cells was significantly increased in COVID-19 patients. Moreover,all ILC subsets displayed a significantly higher frequency of CD69-expressing cells,indicating a heightened state of activation. ILC2s from COVID-19 patients had the highest number of significantly differentially expressed (DE) genes. The most notable genes DE in COVID-19 vs healthy participants included a) genes associated with responses to virus infections and b) genes that support ILC self-proliferation,activation and homeostasis. In addition,differential gene regulatory network analysis revealed ILC-specific regulons and their interactions driving the differential gene expression in each ILC. DiscussionOverall,this study provides mechanistic insights into the characteristics of ILC subsets activated during COVID-19 infection.
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产品号#：
17975
17975RF
产品名：
EasySep™人Pan-ILC富集试剂盒
RoboSep™ 人Pan-ILC富集试剂盒
(Jun 2024)
Nature Immunology 25 8
A humanized mouse that mounts mature class-switched, hypermutated and neutralizing antibody responses
Humanized mice are limited in terms of modeling human immunity,particularly with regards to antibody responses. Here we constructed a humanized (THX) mouse by grafting non-γ-irradiated,genetically myeloablated KitW-41J mutant immunodeficient pups with human cord blood CD34+ cells,followed by 17β-estradiol conditioning to promote immune cell differentiation. THX mice reconstitute a human lymphoid and myeloid immune system,including marginal zone B cells,germinal center B cells,follicular helper T cells and neutrophils,and develop well-formed lymph nodes and intestinal lymphoid tissue,including Peyer’s patches,and human thymic epithelial cells. These mice have diverse human B cell and T cell antigen receptor repertoires and can mount mature T cell-dependent and T cell-independent antibody responses,entailing somatic hypermutation,class-switch recombination,and plasma cell and memory B cell differentiation. Upon flagellin or a Pfizer-BioNTech coronavirus disease 2019 (COVID-19) mRNA vaccination,THX mice mount neutralizing antibody responses to Salmonella or severe acute respiratory syndrome coronavirus 2 Spike S1 receptor-binding domain,with blood incretion of human cytokines,including APRIL,BAFF,TGF-β,IL-4 and IFN-γ,all at physiological levels. These mice can also develop lupus autoimmunity after pristane injection. By leveraging estrogen activity to support human immune cell differentiation and maturation of antibody responses,THX mice provide a platform to study the human immune system and to develop human vaccines and therapeutics. Humanized mice have been a valuable tool for modeling human immunology but are limited in their ability to model human antibody responses. Here the authors present their THX humanized mouse that does model human antibody responses and test its suitability for vaccination and autoimmunity studies.
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EasySep™小鼠TIL（CD45）正选试剂盒
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