Direct stimulation of T cells by membrane vesicles from antigen-presenting cells

Kovář, Marek; Boyman, Onur; Shen, Xin; Hwang, Inkyu; Kohler, Rachel; Sprent, Jonathan

doi:10.1073/pnas.0603466103

Cited by 50 publications

(56 citation statements)

References 31 publications

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“…Both exosomes and plasma-membrane-derived vesicles from APC have been reported to induce potent immune responses in vivo [9,10,25,26]. It is however unknown how peptides are processed to pMHC in these vesicles.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the ER-enriched microsomes do not contain cytosolic or nuclear proteins, which reduces potential side effects. We have not found antimicrosome responses in vitro or in vivo, suggesting that the ER-resident proteins were tolerated.Both exosomes and plasma-membrane-derived vesicles from APC have been reported to induce potent immune responses in vivo [9,10,25,26]. It is however unknown how peptides are processed to pMHC in these vesicles.…”

mentioning

confidence: 99%

“…We demonstrated that microsomes were not endocytozed by DC in vitro. Although we could not exclude the possibility that some of the microsomes in vivo could be endocytosed by APC and the pMHC are indirectly presented by APC to T cells in lymphoid organs, the observed ability to directly activate antigen-specific T cells could be important in microsome vaccines to chronic viral infections or cancer: conditions where endogenous DC are less active in vivo [28,29].After mixing with peptides, the plasma-membrane-derived vesicles also showed the ability to directly interact with T cells and induce responses in vivo [9]. However, as we have shown, the number of peptide-receptive MHC I molecules on the surface of APC is limited due to the presence of pre-processed pMHC I.…”

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Antigen‐loaded ER microsomes from APC induce potent immune responses against viral infection

et al. 2009

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Although matured DC are capable of inducing effective primary and secondary immune responses in vivo, it is difficult to control the maturation and antigen loading in vitro. In this study, we show that ER-enriched microsomal membranes (microsomes) isolated from DC contain more peptide-receptive MHC I and II molecules than, and a similar level of costimulatory molecules to, their parental DC. After loading with defined antigenic peptides, the microsomes deliver antigenic peptide-MHC complexes (pMHC) to both CD4 and CD8 T cells effectively in vivo. The peptide-loaded microsomes accumulate in peripheral lymphoid organs and induce stronger immune responses than peptide-pulsed DC. The microsomal vaccines protect against acute viral infection. Our data demonstrate that peptide-MHC complexes armed microsomes from DC can be an important alternative to DC-based vaccines for protection from viral infection. IntroductionProfessional APC can induce powerful T-cell immune responses by capturing antigens, processing them into peptide-MHC complexes (pMHC) and presenting them to T cells [1]. Together with pMHC, APC also provide cosimulatory signals to T cells, which control the magnitude, quality and memory of the induced immune responses [2]. The understanding of the function of APC led to exploration of novel vaccines with the use of antigenarmed APC against infectious diseases and cancer. In both these cases, T-cell-mediated immunity is essential for eradicating virally infected or malignantly transformed cells, particularly against many of the known infectious agents such as tuberculosis, malaria, herpes simplex, papilloma, HIV, Epstein-Barr and hepatitis C viruses [3]. DC, the most potent APC, have been used to elicit protective T-cell immune response to viral infections and cancer in mice and humans with defined antigens [4]. Although some initial promising results were reported, clinical applications have been limited due to difficulties in the quality control of DC matured in vitro, leading to immunogenic heterogeneity of matured DC in induction versus suppression of T-cell responses. The suppressive function of DC subsets largely results in the induction of T cells producing soluble negative regulators such as IL-10, TGF-b and IDO [5][6][7]. To overcome the Eur. J. Immunol. 2009. 39: 85-95 DOI 10.1002 Cellular immune response 85 difficulties of DC therapy, cell-free antigen-presenting systems have been reported, including membrane vesicles derived from APC such as exosomes, which are secreted from endosomal compartments of APC and microvesicles derived from plasma membranes of APC after sonication [8,9]. Exosomes and microvesicles contain MHC I and II and costimulatory molecules and could induce T-cell responses in vivo when mixed with or pre-loaded with defined peptides [9,10]. However, because it is not known how the pMHCs are processed in these membrane vesicles, both the quality and the quantity of pMHC are difficult to control in the preparation. The MHC molecules on the surface of APC are pre-processed; therefo...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Antigen‐loaded ER microsomes from APC induce potent immune responses against viral infection

et al. 2009

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“…In addition, some studies reported exosomes could affect T cells only when DC existed (29,30). Other studies reported exosomes could affect T cells directly without the assistance of DC (31,32). Recently, studies reported that exosomes could not stimulate the ability of T cells to kill cancer cells but might induce the apoptosis of T cell (10,33,34).…”

Section: The In Vitro Anti-ovarian Cancer Cytotoxic Activity Of the Pmentioning

confidence: 99%

Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity

2011

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Abstract. This study was performed to identify the origin of the ascites-derived exosomes from patients with ovarian cancer and to observe the effect of exosomes on anti-tumor immunity. Exosomes were isolated from the ascites of patients with ovarian epithelial cancer by ultracentrifugation plus density gradient centrifugation. The origin of exosomes was identified by immunoelectronmicroscopy (IEM). The growth curve of the tumor cell line SKOV3 cultured with or without exosomes was analyzed. The apoptosis of autogeneic tumor cells (ATCs) and SKOV3 cells affected by exosomes was measured by flow cytometry (FCM) and light phase contrast microscopy. The cytotoxic effect of the peripheral blood mononuclear cells (PBMCs) stimulated by exosomes and/or dendritic cells (DCs) on ovarian cancer cells was measured using a CCK-8 assay. The levels of IFN-Á released by PBMCs stimulated by exosomes and/or DCs were measured by ELISA. The apoptosis of PBMCs and DCs affected by exosomes was measured by FCM and light microscopy. Whether the mature process of DCs was affected by exosomes was studied by FCM. The ratio of CD4 + T cell and CD8 + T cell were measured by FCM. FasL and TRAIL molecules on exosomes were detected by Western blot analysis. The human FasL antagonistic antibody was used to block the apoptosis of DCs and PBMCs induced by exosomes. The receptors of TRAIL DR4 and DR5 on PBMCs and DCs were detected by FCM. In 41 patients examined, we isolated exosomes from the ascites of 35 patients. We detected TCR, CD20, HLA-DR, B7-2, HER2/neu, CA125 and Histone H 2 A on exosomes. We found that exosomes might impair the cytotoxic activity of PBMCs when DCs are present. We found that exosomes had no effect on the growth and apoptosis of SKOV3 cells. However, exosomes may induce apoptosis of precursors, mature DCs and PBMCs. We found that FasL and TRAIL were present in the exosome suspension and addition of an anti-FasL antibody may decrease the percentage of apoptosis of DCs and PBMCs. We conclude that exosomes exist in ascites of 85.4% of patients with ovarian cancer. Moreover, these exosomes may be of multi-origin. Exosomes had no effect on the growth and apoptosis of tumor cells but impaired the cytotoxic activity of PBMCs in the presence of DCs. Exosomes also may induce apoptosis of the precursors of DCs, DCs and PBMCs. FasL and TRAIL on exosomes may partly account for the apoptosis of cells of the immune system.

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“…86 This opened up the possibility to activate antitumor immune response through the administration of exosomes from dendritic cells bearing tumor antigens. As a result, exosomes can serve as noncellular vaccines activating immune response against tumor cells, and also against pathogenic microbes 87 and parasites.…”

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confidence: 99%

Exosomes as mediators of intercellular communication: clinical implications

Nazimek¹,

Bryniarski²,

Santocki³

et al. 2015

Polish Archives of Internal Medicine

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mainly through: 1) simple membrane-crossing diffusion (eg, transport of steroids); 2) active transport via membrane ion-channels, pumps, or transporting proteins; 3) the formation of synapses including immunological and nerve synapses; and 4) the exchange of cell membrane fragments termed trogocytosis.1 Furthermore, cells communicate in an auto-, para-, and endocrine manner by sensing circulating endogenous bioactive compounds including: 1) proteins (eg, hormones, cytokines), lipoproteins, lipids, and steroids; 2) simpler compounds such as eicosanoids, monoamines (eg, neurotransmitters), endorphins, or cannabinoids; and, finally, 4) extracellular microRNA (miRNA) molecules associated with protein chaperones. The majority of these signaling compounds were found in the content of extracellular vesicles, mainly exosomes. It should be stressed that the interaction of extracellular vesicles with targeted cells can produce varied biological effects mainly resulting from direct exosome-cell stimulation and action of transferred exosome cargo. 2 Exosomes release their content into an acceptorIntroduction Studies of the last decade uncovered the special role of extracellular vesicles, especially exosomes, in local and systemic cell-to-cell communication. Moreover, exosomes were shown to carry various bioactive compounds including proteins, lipids, and diverse RNA molecules. At present, particular emphasis is placed on the extremely high potential of exosomes as prognostic and diagnostic markers as well as therapeutic nanocarriers, especially after demonstration that their cargo and targeting specificity could be manipulated.The current review briefly summarizes the role of exosomes in intercellular signaling pathways orchestrating varied biological mechanisms, with a special focus on the use of exosomes in the diagnosis and treatment of various inflammatory, cardiovascular, metabolic, and neurodegenerative disorders as well as cancer. Modes of cell-to-cell communication AbstrActCells of multicellular organisms exchange informative signals by diverse mechanisms. Recent findings uncovered the special role of extracellular vesicles, especially exosomes, in intercellular communication. Exosomes, present in all tested human bodily fluids, carry various functional compounds including proteins, lipids, and diverse RNA molecules. The composition of exosome cargo in vivo is likely formed by a regulated selection of specific components and can express the current status of the exosome--secreting cell. Therefore, particular emphasis is now placed on the extremely high potential of exosomes as essentially noninvasive prognostic and diagnostic biomarkers, but also as therapeutic nanocarriers, especially after the discovery that their cargo as well as cell-targeting specificity could be shaped in vitro. In addition, targeting the exosomes mediating pathological intercellular communication may also express high therapeutic potential. Hence, numerous studies are conducted to explore the profile and function of exosomes and their cargo ...

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Direct stimulation of T cells by membrane vesicles from antigen-presenting cells

Cited by 50 publications

References 31 publications

Antigen‐loaded ER microsomes from APC induce potent immune responses against viral infection

Antigen‐loaded ER microsomes from APC induce potent immune responses against viral infection

Exosomes in the ascites of ovarian cancer patients: origin and effects on anti-tumor immunity

Exosomes as mediators of intercellular communication: clinical implications

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