Immunodominance of an Antiviral Cytotoxic T Cell Response Is Shaped by the Kinetics of Viral Protein Expression

Probst, Hans Christian; Tschannen, Kathrin; Gallimore, Awen; Martinic, Marianne M.; Basler, Michael; Dumrese, Tilman; Jones, Emma; Broek, Maries van den

doi:10.4049/jimmunol.171.10.5415

Cited by 95 publications

(119 citation statements)

References 62 publications

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“…Predictably, over the course of infection, the levels of LCMV-NP and GP increased over 24 h ( Fig. 2A), and consistent with the previous reports, LCMV-NP was detected earlier than LCMV-GP [19,20]. Our study examined the cross-presentation of NP396, NP205, GP33, and GP276 using primary and pAPC cell lines (Fig.…”

Section: Lcmv-np and Gp Epitopes Are Cross-presented With Different Esupporting

confidence: 88%

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The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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Section: Lcmv-np and Gp Epitopes Are Cross-presented With Different Esupporting

confidence: 88%

“…[20]. Our results show that infected ADC can provide antigens for cross-presentation in a comparable time frame.…”

Section: Discussionmentioning

confidence: 53%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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“…Certain T cell clones may dominate responses by out-competing others for APCs (6,7) by suppressing responses to subdominant epitopes (8,9) or by more efficiently generating IFN␥ (46). Other explanations for immunodominance include the induction of tolerance to certain epitopes (5), physical separation between epitopes (9), kinetics of protein expression (47), and agonist͞antagonist peptide interactions with TCR (48). However, there is little definitive data demonstrating the relative importance of these explanations in vivo.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptidesin vivoand plays an important role in immunodominance

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Brehm

Zendzian

et al. 2006

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

178

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CD8 ؉ T cells respond to short peptides bound to MHC class I molecules. Although most antigenic proteins contain many sequences that could bind to MHC class I, few of these peptides actually stimulate CD8 ؉ T cell responses. Moreover, the T cell responses that are generated often follow a very reproducible hierarchy to different peptides for reasons that are poorly understood. We find that the loss of a single enzyme, endoplasmic reticulum aminopeptidase 1 (ERAP1), in the antigen-processing pathway results in a marked shift in the hierarchy of immunodominance in viral infections, even when the responding T cells have the same T cell receptor repertoire. In mice, ERAP1 is the major enzyme that trims precursor peptides in the endoplasmic reticulum and, in this process, can generate or destroy antigenic peptides. Consequently, when ERAP1 is lost, the immune response to some viral peptides is reduced, to others increased, and to yet others unchanged. Therefore, many epitopes must be initially generated as precursors that are normally trimmed by ERAP1 before binding to MHC class I, whereas others are normally degraded by ERAP1 to lengths that are too short to bind to MHC class I. Moreover, peptide trimming and the resulting abundance of peptide-MHC complexes are dominant factors in establishing immunodominance.antigen presentation ͉ antigen processing ͉ peptidases C ells infected with a virus or otherwise producing foreign proteins can be recognized and eliminated by CD8 ϩ T cells. CD8 ϩ T cells recognize their targets through interactions between their T cell receptor (TCR) and MHC class I on the surface of the target cell. MHC class I is composed of a light chain (␤ 2 -microglobulin), a highly polymorphic heavy chain, and a small peptide that is produced by degradation of intracellular proteins.MHC class I alleles bind to peptides with a particular set of anchor residues that fit into pockets in the MHC class I peptide-binding groove. Virus proteomes typically contain many peptides with anchor residues suitable for particular MHC class I alleles, yet immune responses are generally directed toward a very limited number of epitopes. This phenomenon, in which only a few epitopes are functionally immunogenic, is known as immunodominance and is, as yet, incompletely understood (reviewed in ref. 1). Although many explanations for immunodominance have been proposed (1-9), their relative importance is not well established.The generation of most MHC class I epitopes requires proteolysis by proteasomes in the cytosol. Proteasomes can generate either the mature epitope that is ultimately presented by MHC class I molecules or precursors that are extended by several amino acids at the amino terminus. Such N-extended peptides are further processed by aminopeptidases to generate the final presented epitope. Although a number of peptidases have been proposed to play roles in MHC class I antigen presentation, few have been shown to play a major role in antigen presentation in intact cells. In cell lysates, aminopeptidases, includin...

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“…These observations are important for antigen presentation as studies from our group and others show that the translational efficiency of viral proteins directly affects the generation of rapidly degrading polypeptides (RDPs), which are the primary source of CD8 + T-cell epitopes 7,9,14,15,18,[37][38][39][40][41][42][43][44] . EBNA1 is an ideal model to demonstrate that CD8 + T-cell epitopes are less efficiently processed from a poorly synthesized wild-type EBNA1 generating fewer RDPs compared with a more efficiently synthesized codon-modified EBNA1 where Gquadruplex structures have been destabilized, with a resultant increase in RDPs.…”

Section: Discussionmentioning

confidence: 99%

G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation

et al. 2014

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Viruses that establish latent infections have evolved unique mechanisms to avoid host immune recognition. Maintenance proteins of these viruses regulate their synthesis to levels sufficient for maintaining persistent infection but below threshold levels for host immune detection. The mechanisms governing this finely tuned regulation of viral latency are unknown. Here we show that mRNAs encoding gammaherpesviral maintenance proteins contain within their open reading frames clusters of unusual structural elements, G-quadruplexes, which are responsible for the cisacting regulation of viral mRNA translation. By studying the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1) mRNA, we demonstrate that destabilization of G-quadruplexes using antisense oligonucleotides increases EBNA1 mRNA translation. In contrast, pretreatment with a G-quadruplex-stabilizing small molecule, pyridostatin, decreases EBNA1 synthesis, highlighting the importance of G-quadruplexes within virally encoded transcripts as unique regulatory signals

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Immunodominance of an Antiviral Cytotoxic T Cell Response Is Shaped by the Kinetics of Viral Protein Expression

Cited by 95 publications

References 62 publications

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptidesin vivoand plays an important role in immunodominance

G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation

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