Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing

Tagawa, Takanobu; Albanese, Manuel; Bouvet, Mickaël; Moosmann, Andreas; Mautner, Josef; Heissmeyer, Vigo; Zielinski, Christina E.; Lutter, Dominik; Hoser, Jonathan; Hastreiter, Maximilian; Hayes, Mitchell; Sugden, Bill; Hammerschmidt, Wolfgang

doi:10.1084/jem.20160248

Cited by 107 publications

(133 citation statements)

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“…Recently, we found that multiple viral miRNAs limit the control of infected B cells by CD4 + T cells early in EBV infection (35). Several viral miRNAs reduce secretion of IL-12, expression of HLA class II molecules, and expression of lysosomal enzymes important for antigen presentation to CD4 + T cells.…”

Section: Significancementioning

confidence: 99%

“…Several viral miRNAs reduce secretion of IL-12, expression of HLA class II molecules, and expression of lysosomal enzymes important for antigen presentation to CD4 + T cells. EBV miRNAs also regulate many molecules of potential importance in HLA class I presentation and CD8 + T-cell recognition (35).…”

Section: Significancementioning

confidence: 99%

“…We screened cellular transcripts targeted by EBV miRNAs and likely critical in fending off antiviral CD8 + T cells. To identify potential targets, we performed high-throughput screening with primary B lymphocytes infected with the different EBV strains and a combination of RNA and RNA induced silencing complexes-immunoprecipitation (RISC-IP) sequencing (35). With this approach, we identified IL12B and three genes (IFI30, the IFN-γ-regulated thiol reductase GILT; LGMN, the asparagine endopeptidase AEP alias legumain; and CTSB, the peptidase cathepsin B) encoding lysosomal enzymes and important for CD4 + T-cell differentiation and antigen processing as direct targets of viral miRNAs (35).…”

Section: Ebv Mirnas Inhibit Mhc Class I Antigen Processing and Presenmentioning

confidence: 99%

“…To identify potential targets, we performed high-throughput screening with primary B lymphocytes infected with the different EBV strains and a combination of RNA and RNA induced silencing complexes-immunoprecipitation (RISC-IP) sequencing (35). With this approach, we identified IL12B and three genes (IFI30, the IFN-γ-regulated thiol reductase GILT; LGMN, the asparagine endopeptidase AEP alias legumain; and CTSB, the peptidase cathepsin B) encoding lysosomal enzymes and important for CD4 + T-cell differentiation and antigen processing as direct targets of viral miRNAs (35). Here, we focused on genes consistently inhibited by EBV miRNAs and known to play a role in antigen processing and presentation and cytokine-cytokine receptor interactions or are considered cell adhesion molecules according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway categories (Table 1).…”

Section: Ebv Mirnas Inhibit Mhc Class I Antigen Processing and Presenmentioning

confidence: 99%

“…Presentation of the B*40:01-restricted IED epitope is dependent on active TAP transportation (39), whereas the HLA-A*02:01-restricted epitope FLY is highly hydrophobic and presented TAP-independently (26). In a time course experiment Genes were identified by mRNA sequencing of WT/B95-8 vs. ΔmiR-infected B cells, ranked by z score, and where indicated, confirmed by RISCIPs as described in Tagawa and coworkers (35). IPO7 served as a positive control.…”

Section: Ebv Mirnas Inhibit Mhc Class I Antigen Processing and Presenmentioning

confidence: 99%

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Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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137

133

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Infection with Epstein-Barr virus (EBV) affects most humans worldwide and persists life-long in the presence of robust virus-specific T-cell responses. In both immunocompromised and some immunocompetent people, EBV causes several cancers and lymphoproliferative diseases. EBV transforms B cells in vitro and encodes at least 44 microRNAs (miRNAs), most of which are expressed in EBV-transformed B cells, but their functions are largely unknown. Recently, we showed that EBV miRNAs inhibit CD4 + T-cell responses to infected B cells by targeting IL-12, MHC class II, and lysosomal proteases. Here we investigated whether EBV miRNAs also counteract surveillance by CD8 + T cells. We have found that EBV miRNAs strongly inhibit recognition and killing of infected B cells by EBV-specific CD8 + T cells through multiple mechanisms. EBV miRNAs directly target the peptide transporter subunit TAP2 and reduce levels of the TAP1 subunit, MHC class I molecules, and EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8 + T cells. Moreover, miRNAmediated down-regulation of the cytokine IL-12 decreases the recognition of infected cells by EBV-specific CD8 + T cells. Thus, EBV miRNAs use multiple, distinct pathways, allowing the virus to evade surveillance not only by CD4 + but also by antiviral CD8 + T cells.adaptive immunity | immune evasion | herpesvirus | CD8 T cells | microRNA E pstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects the majority of the human population worldwide. Although EBV infection persists for life, most carriers remain asymptomatic due to a stringent control by virus-specific immunity. An important component of this immunity is EBV-specific CD8 + T cells, which often expand to high numbers in healthy carriers or after primary infection. Conversely, the absence of EBV-specific CD8 + T cells predicts the emergence of EBVassociated disease in patients after stem cell transplantation or when afflicted with AIDS (1-3). Dangerous EBV-mediated complications can be reversed or prevented by transfer of EBVspecific T cells (4, 5), which further confirms the important role of continuous T-cell control of EBV infection. Among EBVspecific T cells, CD8 + T cells predominate; about 0.05-1% of all CD8 + T cells in healthy donors are typically specific for EBV latent antigens and about twice as many for lytic antigens (6, 7).EBV predominantly infects B cells and establishes a latent infection before production of progeny virus becomes possible (8). Four distinct programs of EBV latent infection have been defined according to their expression profiles of latent viral genes (9-11). One of these programs, known as latency III or the "growth program," is characterized by the expression of a restricted set of approximately eight viral proteins, which activate B cells and drive their proliferation, thus increasing the viral reservoir. Latency III is found in EBV-associated malignancies in immunosuppressed patients (9) and likely reemerges continuously in healthy carriers (9, 12), indicati...

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Ebv Mirnas Inhibit Mhc Class I Antigen Processing and Presenmentioning

confidence: 99%

Section: Ebv Mirnas Inhibit Mhc Class I Antigen Processing and Presenmentioning

confidence: 99%

Section: Ebv Mirnas Inhibit Mhc Class I Antigen Processing and Presenmentioning

confidence: 99%

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Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Albanese

Tagawa

Bouvet

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

133

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Herpesviruses

Cohen¹

2022

Holland‐Frei Cancer Medicine

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Overview Eight herpesviruses have been isolated from humans: two of these, Epstein–Barr virus (EBV), and Kaposi sarcoma‐associated herpesvirus (KSHV), are associated with human tumors. EBV has been detected in lesions from patients with posttransplant lymphoproliferative disease, nasopharyngeal and some types of gastric carcinoma, Burkitt lymphoma, Hodgkin lymphoma, and certain other lymphoid tumors. KSHV is associated with Kaposi sarcoma, primary effusion lymphoma, and Castleman disease. Each of these viruses encodes proteins important for establishment of latency, transforming cells, and evading the immune system.

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Immunomodulatory roles of human herpesvirus‐encoded microRNA in host‐virus interaction

Naqvi

2019

Reviews in Medical Virology

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SummaryHuman herpesviruses (HHV) are large, double stranded, DNA viruses with high seroprevalence across the globe. Clinical manifestation of primary HHV infection resolve shortly, however, this period is prolonged in immunocompromised patients or individuals with suppressed immunity. Examining molecular mechanisms of HHV‐encoded virulence factors can provide finer details of HHV‐host interaction. A unique genetic feature of most members of HHV is that they encode multiple microRNAs (miR). In this review, I will provide mechanistic insights into the immunomodulatory functions of herpesvirus‐encoded viral miR (v‐miR) that favor viral persistence and spread by ingenious immune evasion schemes. Similar to host miR, v‐miR can simultaneously regulate expression of multiple transcripts including host‐ and virus‐derived. V‐miRs, by virtue of their direct interaction with various transcripts, can regulate expression of critical components of host innate and adaptive immune system. V‐miRs are also exported through exosomal route and gain entry into various cells even at distant sites, thereby allowing HHV to manipulate cellular and tissue immunity. Targeting v‐miR may serve as a novel and promising therapeutic candidate to mitigate HHV‐mediated clinical manifestations.

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Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing

Cited by 107 publications

References 61 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Herpesviruses

Immunomodulatory roles of human herpesvirus‐encoded microRNA in host‐virus interaction

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Epstein-Barr viral miRNAs inhibit antiviral CD4+ T cell responses targeting IL-12 and peptide processing

Cited by 107 publications

References 61 publications

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 + T cells

Herpesviruses

Immunomodulatory roles of human herpesvirus‐encoded microRNA in host‐virus interaction

Contact Info

Product

Resources

About

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells

Epstein–Barr virus microRNAs reduce immune surveillance by virus-specific CD8 ⁺ T cells