mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.

Recent studies have shown that virally encoded mRNA sequences of genome maintenance proteins from herpesviruses contain clusters of unusual structural elements, G-quadruplexes, which modulate viral protein synthesis. Destabilization of these G-quadruplexes can override the inhibitory effect on self-...

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Main Authors: Judy T Tellam, Jie Zhong, Lea Lekieffre, Purnima Bhat, Michelle Martinez, Nathan P Croft, Warren Kaplan, Ross L Tellam, Rajiv Khanna
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2014-10-01
Series:PLoS Pathogens
Online Access:http://europepmc.org/articles/PMC4192603?pdf=render
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spelling doaj-bdf49c44f93742ea967d225a8ab817cf2020-11-25T01:06:31ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742014-10-011010e100442310.1371/journal.ppat.1004423mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.Judy T TellamJie ZhongLea LekieffrePurnima BhatMichelle MartinezNathan P CroftWarren KaplanRoss L TellamRajiv KhannaRecent studies have shown that virally encoded mRNA sequences of genome maintenance proteins from herpesviruses contain clusters of unusual structural elements, G-quadruplexes, which modulate viral protein synthesis. Destabilization of these G-quadruplexes can override the inhibitory effect on self-synthesis of these proteins. Here we show that the purine-rich repetitive mRNA sequence of Epstein-Barr virus encoded nuclear antigen 1 (EBNA1) comprising G-quadruplex structures, limits both the presentation of MHC class I-restricted CD8(+) T cell epitopes by CD11c(+) dendritic cells in draining lymph nodes and early priming of antigen-specific CD8(+) T-cells. Destabilization of the G-quadruplex structures through codon-modification significantly enhanced in vivo antigen presentation and activation of virus-specific T cells. Ex vivo imaging of draining lymph nodes by confocal microscopy revealed enhanced antigen-specific T-cell trafficking and APC-CD8(+) T-cell interactions in mice primed with viral vectors encoding a codon-modified EBNA1 protein. More importantly, these antigen-specific T cells displayed enhanced expression of the T-box transcription factor and superior polyfunctionality consistent with the qualitative impact of translation efficiency. These results provide an important insight into how viruses exploit mRNA structure to down regulate synthesis of their viral maintenance proteins and delay priming of antigen-specific T cells, thereby establishing a successful latent infection in vivo. Furthermore, targeting EBNA1 mRNA rather than protein by small molecules or antisense oligonucleotides will enhance EBNA1 synthesis and the early priming of effector T cells, to establish a more rapid immune response and prevent persistent infection.http://europepmc.org/articles/PMC4192603?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Judy T Tellam
Jie Zhong
Lea Lekieffre
Purnima Bhat
Michelle Martinez
Nathan P Croft
Warren Kaplan
Ross L Tellam
Rajiv Khanna
spellingShingle Judy T Tellam
Jie Zhong
Lea Lekieffre
Purnima Bhat
Michelle Martinez
Nathan P Croft
Warren Kaplan
Ross L Tellam
Rajiv Khanna
mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.
PLoS Pathogens
author_facet Judy T Tellam
Jie Zhong
Lea Lekieffre
Purnima Bhat
Michelle Martinez
Nathan P Croft
Warren Kaplan
Ross L Tellam
Rajiv Khanna
author_sort Judy T Tellam
title mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.
title_short mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.
title_full mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.
title_fullStr mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.
title_full_unstemmed mRNA Structural constraints on EBNA1 synthesis impact on in vivo antigen presentation and early priming of CD8+ T cells.
title_sort mrna structural constraints on ebna1 synthesis impact on in vivo antigen presentation and early priming of cd8+ t cells.
publisher Public Library of Science (PLoS)
series PLoS Pathogens
issn 1553-7366
1553-7374
publishDate 2014-10-01
description Recent studies have shown that virally encoded mRNA sequences of genome maintenance proteins from herpesviruses contain clusters of unusual structural elements, G-quadruplexes, which modulate viral protein synthesis. Destabilization of these G-quadruplexes can override the inhibitory effect on self-synthesis of these proteins. Here we show that the purine-rich repetitive mRNA sequence of Epstein-Barr virus encoded nuclear antigen 1 (EBNA1) comprising G-quadruplex structures, limits both the presentation of MHC class I-restricted CD8(+) T cell epitopes by CD11c(+) dendritic cells in draining lymph nodes and early priming of antigen-specific CD8(+) T-cells. Destabilization of the G-quadruplex structures through codon-modification significantly enhanced in vivo antigen presentation and activation of virus-specific T cells. Ex vivo imaging of draining lymph nodes by confocal microscopy revealed enhanced antigen-specific T-cell trafficking and APC-CD8(+) T-cell interactions in mice primed with viral vectors encoding a codon-modified EBNA1 protein. More importantly, these antigen-specific T cells displayed enhanced expression of the T-box transcription factor and superior polyfunctionality consistent with the qualitative impact of translation efficiency. These results provide an important insight into how viruses exploit mRNA structure to down regulate synthesis of their viral maintenance proteins and delay priming of antigen-specific T cells, thereby establishing a successful latent infection in vivo. Furthermore, targeting EBNA1 mRNA rather than protein by small molecules or antisense oligonucleotides will enhance EBNA1 synthesis and the early priming of effector T cells, to establish a more rapid immune response and prevent persistent infection.
url http://europepmc.org/articles/PMC4192603?pdf=render
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