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Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection.

ABSTRACT: Hepatitis C virus (HCV) is a global health concern that can cause severe liver disease, such as cirrhosis and hepatocellular carcinoma. Control of HCV requires vigorous T-cell responses, yet CD4+ T cells in chronic HCV patients are dysfunctional. T follicular regulatory (Tfr) cells are a subset of regulatory T cells that suppress T follicular helper (Tfh) cells and the generation of high affinity antibody-producing B cells. In this study, we examined the accumulation of Tfr cells in the liver compartment during chronic HCV infection and defined the cellular and molecular mechanisms underlying their expansion. Our analysis revealed a substantial population of Tfr cells in livers of chronic HCV patients that is absent in liver tissues from nonviral hepatitis or healthy subjects. Coculture of PBMCs from healthy subjects with HCV-infected hepatoma cells resulted in preferential expansion of circulating Tfr cells, leading to suppression of Tfh cells. Additionally, coculture of tonsillar cells with infected hepatoma cells lead to an expansion of germinal center Tfr. Notably, expansion was mediated by transforming growth factor beta (TGF-?)-containing exosomes released from HCV-infected hepatocytes given that blockade of exosome-associated TGF-? or inhibition of exosome release abrogated Tfr expansion. CONCLUSION:These results show that liver-derived exosomes play a pivotal role in the accumulation of Tfr cells, likely leading to suppression of Tfh responses in HCV-infected patients. Our study identifies a novel pathway in which HCV infection in hepatocytes exacerbates Tfr cell responses to subvert antiviral immunity. (Hepatology 2018;67:71-85).

SUBMITTER: Cobb DA

PROVIDER: S-EPMC5739980 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection.

Cobb Dustin A DA Kim Ok-Kyung OK Golden-Mason Lucy L Rosen Hugo R HR Hahn Young S YS

Hepatology (Baltimore, Md.) 20171115 1

Hepatitis C virus (HCV) is a global health concern that can cause severe liver disease, such as cirrhosis and hepatocellular carcinoma. Control of HCV requires vigorous T-cell responses, yet CD4<sup>+</sup> T cells in chronic HCV patients are dysfunctional. T follicular regulatory (Tfr) cells are a subset of regulatory T cells that suppress T follicular helper (Tfh) cells and the generation of high affinity antibody-producing B cells. In this study, we examined the accumulation of Tfr cells in t ...[more]

PMID: 28749570

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Project description:Virus-infected cells can regulate non-permissive bystander cells, but the precise mechanisms remain incompletely understood. Here we report that this process can be mediated by transfer of viral RNA-loaded exosomes shed from infected cells to myeloid-derived suppressor cells (MDSCs), which in turn regulate the differentiation and function of T cells during viral infection. Specifically, we demonstrated that patients with chronic hepatitis C virus (HCV) infection exhibited significant increases in T follicular regulatory (TFR) cells and decreases in T follicular helper (TFH) cells. These MDSC-mediated T-cell dysregulations resulted in an increased ratio of TFR/TFH and IL-10 production in peripheral blood. Specifically, co-culture of MDSCs derived from HCV patients with healthy peripheral blood mononuclear cells (PBMCs) induced expansion of TFR, whereas depletion of MDSCs from PBMCs of HCV patients reduced the increases in TFR frequency and IL-10 production, and promoted the differentiation of IFN-?-producing TFH cells. Importantly, we found that exosomes isolated from the plasma of HCV patients and supernatant of HCV-infected hepatocytes could drive monocytic myeloid cell differentiation into MDSCs. These exosomes were enriched in tetraspanins, such as CD63 and CD81, and contained HCV RNA, but exosomes isolated from patients with antiviral treatment contained no HCV RNA and could not induce MDSC differentiation. Notably, these HCV RNA-containing exosomes (HCV-Exo) were sufficient to induce MDSCs. Furthermore, incubation of healthy myeloid cells with these HCV-Exo inhibited the expression of miR-124, whereas reconstitution of PBMCs with miR-124 abolished the effects of HCV-Exo on MDSC induction. Taken together, these results indicate that HCV-associated exosomes can transfer immunomodulatory viral RNA from infected cells to neighboring immune cells and trigger MDSC expansion, which subsequently promotes TFR differentiation and inhibits TFH function. This study reveals a previously unrecognized path that represents a novel mechanism of immune dysregulation during chronic viral infection.

Project description:BackgroundTrimethylamine-N-oxide (TMAO) has been proven to be a new proatherogenic compound for promoting inflammation and endothelial dysfunction. Hepatocyte-derived exosomes (Exos), including those derived from hepatocytes, play a pivotal role in the regulation of inflammation and endothelial function. As TMAO is produced in the liver, hepatocytes may be the potential target of TMAO. However, it is not yet clear whether TMAO can directly stimulate hepatocytes to produce Exos to mediate the detrimental effects of TMAO on vascular endothelial cells (VECs).MethodsHepatocytes treated with TMAO and Exos (TMAO-Exos) were isolated from the supernatant, and added to human aortic endothelial cells (HAECs). The expressions of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) were detected by quantitative polymerase chain reaction (qPCR). Cell apoptosis was evaluated using Hoechst 33342 staining and flow cytometry assay, and cell migration was assessed by scratch and transwell assay. C57BL/6 mice were treated with Exos for 24 h and the thoracic aortas were isolated, then the in vitro aortic ring bioassay was conducted to determine the changes of vasodilation. The expressions of cluster of differentiation 81, tumor susceptibility gene 101, nuclear factor-kappa B (NF-κB) p65, and Phospho-NF-κB p65 were detected by western blotting. The micro ribonucleic acid (miRNA) profiles of the Exos were then identified using RNA-sequencing and validated by qPCR. The miRNA-messenger RNA networks were constructed, and the biological functions of the target genes were annotated using bioinformatics methods.ResultsTMAO was found to stimulate hepatocytes to release Exos that could be taken up by HAECs, thus inducing inflammation and cell apoptosis, impairing cell migration, and inhibiting endothelium-dependent vasodilation. Additionally, the miRNAs such as miR-302d-3p carried by the TMAO-Exos were quite different to those in the TMAO-free group. A further analysis showed that the potential target genes for these miRNAs, such as mitogen-activated protein kinase 8, caspase 9 and BCL2-like 11, appeared to be involved with inflammation and endothelial function. Finally, we found that NF-κB signaling could be activated by TMAO-Exos.ConclusionsThese novel findings provide evidence that TMAO can indirectly talk to VECs by promoting hepatocytes to produce Exos that carry important genetic information.

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Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection.

Publications

Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection.

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