Exosomal‐like vesicles with immune‐modulatory features are present in human plasma and can induce CD4+ T‐cell apoptosis in vitro

Ren, Yana; Yang, Jie; Xie, Ruiqin; Gao, Li; Yang, Yiming; Fan, Huimin; Qian, Kun

doi:10.1111/j.1537-2995.2010.02909.x

Cited by 44 publications

(34 citation statements)

References 58 publications

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“…36 The function of immune cells in response to EVs is controversial, and EVs may skew the immune system toward suppression or stimulation. [37][38][39] It has been demonstrated that stimulation of macrophages with platelet-derived ectosomes drives them to an antiinflammatory profile. 6 Additionally, tumor-derived EVs are immunosuppressive and can inhibit the expansion of IL-2-induced CTL and natural killer cells, but not regulatory T cells, in PBMC cultures.…”

Section: Discussionmentioning

confidence: 99%

Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro

Danesh

Inglis

Jackman

et al. 2014

Blood

214

246

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• Exosomes in blood are proinflammatory and may contribute to transfusionrelated immune modulation.• Exosomes act via antigenpresenting cells to potentiate T-cell survival and mitogeninduced proliferation.Extracellular vesicles (EVs) are small, double membrane vesicles derived from leukocytes, platelets, and cells of other tissues under physiological or pathological conditions. Generation of EVs in stored blood is thought to be associated with adverse effects and potentially immunosuppression in blood transfusion recipients. We measured the quantity and cells of origin for EVs isolated from stored red blood cell (RBC) units and tested whether they had any effects on T-cell-mediated immune responses. Mixing peripheral blood mononuclear cells (PBMCs) with EVs resulted in secretion of proinflammatory cytokines and chemokines and increased survival of unstimulated PBMCs. EVs augmented mitogen-induced CD4 1 and CD8 1 T-cell proliferation in an antigenpresenting cell (APC)-dependent manner. We demonstrated that EVs interacted primarily with monocytes and induced proinflammatory cytokine secretion. We also showed that the exosome fraction of EVs and not larger microvesicles was responsible for induction of TNF-a production by monocytes. Furthermore, blockade of CD40 or CD40L accessory molecules largely neutralized the EV augmentation of T-cell responses, implying a role for cell-cell interaction between T cells and EV-activated monocytes. Contrary to our hypothesis, the data demonstrate that EVs isolated from RBC units increase the potency of APCs and boost mitogen-driven T-cell proliferative responses. (Blood. 2014;123(5):687-696)

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Section: Discussionmentioning

confidence: 99%

Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro

Danesh

Inglis

Jackman

et al. 2014

Blood

214

246

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“…Strengthening this hypothesis, the exosomes produced by canonical WNT3A displayed a different content as compared to those produced by non-canonical WNT5A signaling. Or it could be explained by the recent finding that indeed Wnt proteins (WNT3A and WNT5A) are secreted on exosomes [54,55]. It has long been known in the Wnt field that WNT5A can induce expression of it self.…”

Section: Discussionmentioning

confidence: 99%

WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells

et al. 2014

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BackgroundWnt proteins are important for developmental processes and certain diseases. WNT5A is a non-canonical Wnt protein that previously has been shown to play a role in the progression of malignant melanoma. High expression of WNT5A in melanoma tumors correlates to formation of distant metastasis and poor prognosis. This has partly been described by the findings that WNT5A expression in melanoma cell lines increases migration and invasion.MethodsMalignant melanoma cell lines were treated with rWNT5A or WNT5A siRNA, and mRNA versus protein levels of soluble mediators were measured using RT-PCR, cytokine bead array and ELISA. The induced signaling pathways were analyzed using inhibitors, Rho-GTPase pull down assays and western blot. Ultracentrifugation and electron microscopy was used to analyze microvesicles. Gene expression microarray data obtained from primary malignant melanomas was used to verify our data.ResultsWe show that WNT5A signaling induces a Ca2+-dependent release of exosomes containing the immunomodulatory and pro-angiogenic proteins IL-6, VEGF and MMP2 in melanoma cells. The process was independent of the transcriptional machinery and depletion of WNT5A reduced the levels of the exosome-derived proteins. The WNT5A induced exosomal secretion was neither affected by Tetanus toxin nor Brefeldin A, but was blocked by the calcium chelator Bapta, inhibited by a dominant negative version of the small Rho-GTPase Cdc42 and was accompanied by cytoskeletal reorganization. Co-cultures of melanoma/endothelial cells showed that depletion of WNT5A in melanoma cells decreased endothelial cell branching, while stimulation of endothelial cells with isolated rWNT5A-induced melanoma exosomes increased endothelial cell branching in vitro. Finally, gene expression data analysis of primary malignant melanomas revealed a correlation between WNT5A expression and the angiogenesis marker ESAM.ConclusionsThese data indicate that WNT5A has a broader function on tumor progression and metastatic spread than previously known; by inducing exosome-release of immunomodulatory and pro-angiogenic factors that enhance the immunosuppressive and angiogenic capacity of the tumors thus rendering them more aggressive and more prone to metastasize.

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“…Therefore, the analysis of exosomes for specific tumour-biomarkers can help in the early detection of cancer before it develops into a full-grown metastasized tumour and causes mortality [6]. Furthermore, Ren and colleagues were able to show that exosomes present in human plasma displayed a variety of shapes and exhibit the exosome marker protein CD81 besides CD63, along with other members of MHC Class II including CD86, Wnt3a, Wnt5a and FasL which are normally known as the cell signal transduction molecules [11]. Plasma exosomes were also shown to participate in the inhibition of CD4+ T cells involved in the immune system.…”

Section: Exosomes As Potential Biomarkers In Cancer Identification Anmentioning

confidence: 98%

“…Plasma exosomes were also shown to participate in the inhibition of CD4+ T cells involved in the immune system. They possess the ability to induce suppression, in dose-dependent manner, of the active CD4+ T cells and their proliferation in the plasma, leading to their natural apoptosis in the body [11]. Moreover, Salma Khan and colleagues researched on the levels of Exosomal Survivin in patients with prostate cancer and in control patients, derived from their plasma.…”

Section: Exosomes As Potential Biomarkers In Cancer Identification Anmentioning

confidence: 99%

The Reliability of Plasma Exosome Concentrations in Healthy Male Individuals

Abu-Seer¹

2017

JHS

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Exosomes are nanometer sized vesicles (30-100 nm), released from cells following the fusion of multivesicular bodies with the plasma membrane. Exosomes have a major role in intracellular communication, immune response modulation, physiological and pathological functions, and an important use in different drug therapies. Moreover, they have been identified as potential biomarkers and are involved in cancer and many other disease processes. Despite the developments in this area, no studies exist that assess the variability of plasma exosomes measures within and between subjects. The purpose of this study was to assess within and between day variability of plasma exosomes concentration in healthy individuals. Also, the stability of exosomes during freeze/thawing cycles was measured in this study. Eleven healthy men were assessed for reliability of exosome concentrations taken over the same sampling period, over 10 hours of a day and over five days. Exosomes were isolated by differential ultracentrifugation and characterized by their size distribution and morphology by electron microscopy and using the Nanosight tracking analysis respectively. Mean plasma exosome values were1.505-2.245 × 10^8/mL). Within day variability was not significantly different (P = 0.95), and between day variability was not significantly different (P = 0.42). The interclass correlation coefficients (ICC) of 0.80 for within sample showed good reliability; ICC of 0.84 for between day plasma exosomes concentrations showed good reliability, and the within day ICC of 0.70 showed a moderate reliability. There was no significant difference observed in using fresh or frozen plasma in exosome quantification or exosome concentration. The statistics show that there is little significant variability in plasma exosome concentrations taken over a single sampling period, over a day or between days, which is vital for plasma exosome studies.

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Exosomal‐like vesicles with immune‐modulatory features are present in human plasma and can induce CD4+ T‐cell apoptosis in vitro

Abstract: Exosomes present in human plasma contain immunity-associated molecules and can induce CD4+ T-cell apoptosis in vitro. Plasma exosomes have the capacity to influence immune responses.

Cited by 44 publications

References 58 publications

Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro

Exosomes from red blood cell units bind to monocytes and induce proinflammatory cytokines, boosting T-cell responses in vitro

WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells

The Reliability of Plasma Exosome Concentrations in Healthy Male Individuals

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