EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance

Jiang, Lingling; Shen, Yingying; Guo, Dongyun; Yang, Diya; Liu, Jiajun; Fei, Xuefeng; Yang, Yu‐Guang; Zhang, Buyi; Lin, Zifan; Yang, Fei; Wang, Xiaojian; Wang, Keyi; Wang, Jianli; Cai, Zhijian

doi:10.1038/ncomms13045

Cited by 108 publications

(123 citation statements)

References 44 publications

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“…Hydrolyzing ATP to Adenosine In Vitro Our previous study had shown that EVs from murine spleens (Sp-EVs) contain transforming growth factor (TGF)-b1 (Jiang et al, 2016). Accordingly, we tested whether Sp-EVs could inhibit CD8 + T cell proliferation in vitro.…”

Section: Cd19 + Evs Inhibit Cd8 + T Cell Proliferation Bymentioning

confidence: 99%

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Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses

et al. 2019

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Graphical Abstract Highlights d CD19 + EVs through CD39 and CD73 hydrolyze ATP from tumor cells into adenosine d CD19 + EVs blunt post-chemotherapeutic CD8 T cell responses via adenosine d Tumor B cells produce more EVs by enhancing HIF-1a-mediated Rab27a transcription d IEBVs-Rab27a siRNA is a potential tool for improving chemotherapeutic effect SUMMARY Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19 + extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8 + T cell responses. Serum CD19 + EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19 + EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1a (HIF-1a) promoted B cells to release CD19 + EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1a deficiency in B cells inhibited CD19 + EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD Prkdc scid Il2rg À/À mice. Thus, decreasing CD19 + EVs holds high potential to improve the chemotherapeutic antitumor effect.

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Section: Cd19 + Evs Inhibit Cd8 + T Cell Proliferation Bymentioning

confidence: 99%

“…For EV or iEBV flow cytometry analysis, EVs or iEBVs were coated onto 4-mm-diameter aldehyde-sulfate latex beads, as described previously (Jiang et al, 2016). The EV-coated beads were stained with the corresponding fluorescence-labeled Abs for 30 min on ice.…”

Section: Flow Cytometrymentioning

confidence: 99%

Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses

et al. 2019

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“…Kanazawa et al found that TGF-b2 and TGF-b3 expression was elevated in lamina propria lymphocytes of active UC and CD patients [20]. Moreover, the intestinal epithelium can produce TGF-b-containing extracellular vesicles [21]. Therefore, TGF-b levels are increased in IBD tissues, but this may not be sufficient to counteract the ongoing inflammation.…”

Section: Tgf-b In Ibd Tgf-b Productionmentioning

confidence: 99%

“…A recent study revealed that TGF-b-containing extracellular vesicles released by epithelial cells induced Treg differentiation and inhibited colitis by binding to EpCAM ? epithelial cells [21]. Therefore, epithelial cells also play an important role in immune homeostasis in a TGF-b-dependent manner.…”

Section: Epithelium and Extracellular Matrixmentioning

confidence: 99%

TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

2017

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Inflammatory bowel disease (IBD) is defined as chronic intestinal inflammation, and includes ulcerative colitis and Crohn's disease. Multiple factors are involved in the pathogenesis of IBD, and the condition is characterized by aberrant mucosal immune reactions to intestinal microbes in genetically susceptible hosts. Transforming growth factor-b (TGF-b) is an immune-suppressive cytokine produced by many cell types and activated by integrins. Active TGF-b binds to its receptor and regulates mucosal immune reactions through the TGF-b signaling pathway. Dysregulated TGF-b signaling is observed in the intestines of IBD patients. TGF-b signal impairment in specific cell types, such as T-cells and dendritic cells, results in spontaneous colitis in mouse models. In addition, specific intestinal microbes contribute to immune homeostasis by modulating TGF-b production. In this review, we describe the role of TGF-b in intestinal immunity, focusing on immune cells, epithelium, and intestinal microbes. In addition, we present potential therapeutic strategies for IBD that target TGF-b.

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“…Similar to early beliefs about EVs, non-coding RNA was also originally thought to be cellular waste and was disregarded for its assumed lack of a biological role (10). Ironically, both EVs and non-coding RNAs are now implicated in various disease states including cancer (11, 12), cardiovascular (13) and neuronal diseases (14). We refer the reader to the many excellent reviews on therapeutic EVs (15–18).…”

Section: Introductionmentioning

confidence: 99%

Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading

et al. 2017

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Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics.

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EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance

Cited by 108 publications

References 44 publications

Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses

Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses

TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota

Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading

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