Cytotoxic T Cell Recognition of the SV40 Tumor Antigen: A Note of Caution

Gooding, Linda R.; apos, O; Connell, Kelly; Geib, R; Pipas, James M.

doi:10.1016/b978-0-12-551855-0.50102-9

Cited by 5 publications

(6 citation statements)

References 26 publications

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“…In this manuscript we provide evidence confirming and extending previous observations by others concerning the processing and presentation of cryptic epitopes (9)(10)(11)(12)(13)(14)42). Our in vitro presentation data concurs with the results of Fetten et al and provides the additional support of a third nucleoprotein epitope, NP366_374.…”

Section: Discussionsupporting

confidence: 91%

“…Immunofluoresence staining of cells infected with the vac recombinants, using an antibody that precipitates NPlqs8 (HB-65), yielded no specific signal and initial NP-immunoprecipitations from cells infected with the vac recombinants, using monoclonal antibodies having complementary specificities, did not yield any specific bands (data not shown). having been shifted out of the conventional RF (10,11,13,14). To determine whether this was true for our constructs using the vac expression system, each was tested for presentation of all three NP epitopes.…”

Section: Construction Of Out-of-frame Epitopes In Influenza Nudeoprotmentioning

confidence: 99%

“…More surprisingly, evidence exists that questions the basic assumption that epitopes must to be encoded in primary open reading frames. Examples include the presentation of epitopes that follow stop codons (9), are encoded in alternate translation reading frames (10)(11)(12)(13), are presented in the absence of any obvious initiation codons (14) or are even processed and presented in the apparent absence of a related promoter (15). Explanations that have been proposed to account for these unusual circumstances include ribosomal frameshifting (11,13), alternative translation initiation codons (14) and the possibility of subgenic transcription events (the pepton hypothesis; 16).…”

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confidence: 99%

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Ribosomal scanning past the primary initiation codon as a mechanism for expression of CTL epitopes encoded in alternative reading frames.

Bullock

Eisenlohr

1996

The Journal of Experimental Medicine

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SummaryAn increasing amount of evidence has shown that epitopes restricted to MHC class I molecules and recognized by CTL need not be encoded in a primary open reading frame (OR.F). Such epitopes have been demonstrated after stop codons, in alternative reading frames (RF) and within introns. We have used a series of frameshifts (FS) introduced into the Influenza A/PR/ 8/34 nucleoprotein (NP) gene to confirm the previous in vitro observations of cryptic epitope expression, and show that they are sufficiently expressed to prime immune responses in vivo. This presentation is not due to sub-dominant epitopes, transcription from cryptic promoters beyond the point of the FS, or internal initiation of translation. By introducing additional mutations to the construct exhibiting the most potent presentation, we have identified initiation codon readthrough (termed scanthrough here, where the scanning ribosome bypasses the conventional initiation codon, initiating translation further downstream) as the likely mechanism of epitope production. Further nmtational analysis demonstrated that, while it should operate during the expression of wild-type (WT) protein, scanthrough does not provide a major source of processing substrate in our system. These findings suggest (i) that the full array of self-and pathogen-derived epitopes available during thymic selection and infection has not been fully appreciated and (it) that cryptic epitope expression should be considered when the specificity of a CTL response cannot be identified or in therapeutic situations when conventional CTL targets are limited, as may be the case with latent viral infections and transformed cells. Finally, initiation codon readthrough provides a plausible explanation for the presentation of exocytic proteins by MHC class I molecules.

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Section: Discussionsupporting

confidence: 91%

Section: Construction Of Out-of-frame Epitopes In Influenza Nudeoprotmentioning

confidence: 99%

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confidence: 99%

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Ribosomal scanning past the primary initiation codon as a mechanism for expression of CTL epitopes encoded in alternative reading frames.

Bullock

Eisenlohr

1996

The Journal of Experimental Medicine

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“…It was puzzling how the cells produced the peptides because the transfected DNA fragments lacked obvious transcriptional and translational control elements such as promoters or translation initiation codons. Other examples of unexpected pMHC I were also discovered in the SV40 and influenza viruses (21, 22). Although not immediately appreciated at the time, each of these unexpected examples of pMHC I was a likely result of cryptic translation mechanisms as definitively established by our studies on the presentation of peptides encoded in alternate translational reading frames (23–26).…”

Section: Discovery Of Cryptic Peptides In the Pmhc I Repertoirementioning

confidence: 91%

“…Thus it was very likely that cryptic pMHC I would also play a role in immunity to pathogens. The two examples of cryptic epitopes referred to above are derived from the influenza and SV40 viruses that elicited T cell responses albeit during experimental manipulations (21, 22). More recently, T cells specific for non-conventional epitopes have been identified as encoded in ARFs of the murine AIDS viral mRNAs underscoring the importance of cryptic pMHC I in immune surveillance (27, 28).…”

Section: Immunological Significance Of Cryptic Translationmentioning

confidence: 99%

Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance

Starck

Shastri

2016

Immunological Reviews

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Summary Effective immune surveillance by CD8+ cytotoxic T cells of intracellular microbes and cancer depends upon the antigen presentation pathway. This pathway produces an optimal peptide repertoire for presentation by MHC class I molecules (pMHC I) on the cell surface. We have known for years that the pMHC I repertoire is a reflection of the intracellular protein pool. However, many studies have revealed that pMHC I present peptides not only from precursors encoded in open-reading frames of mRNA transcripts but also cryptic peptides encoded in apparently “untranslated” regions. These sources vastly increase the availability of peptides for presentation and immune evasion. Here, we review studies on the composition of the cryptic pMHC I repertoire, the immunological significance of these pMHC I, and the novel translational mechanisms that generate cryptic peptides from unusual sources.

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Recognition of out‐of‐frame major histocompatibility complex class I‐restricted epitopes in vivo

1996

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In the course of constructing a recombinant vaccinia virus encoding the influenza A nucleoprotein (NP) gene preceded by the hemagglutinin leader sequence, we isolated a single base-pair deletion mutant which gave rise to L+NP(1-159) in which only the first 159 amino acids were in frame. Despite this, when we infected target cells, we found that the point mutant was able to sensitize them for lysis not only by cytotoxic T cells recognizing residues 50-58 (the in-frame portion), but also by CTL to epitopes which are downstream of the mutation (366-374 and 378-386). Furthermore, normal C57BL/6 mice can be primed with the frameshift NP to recognize the immunodominant Db-restricted epitope 366-374 (which is out of frame). Experiments in which the mutant gene product was processed in the endoplasmic reticulum of target cells suggested that the apparent suppression occurred during polypeptide extension.

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Cytotoxic T Cell Recognition of the SV40 Tumor Antigen: A Note of Caution

Cited by 5 publications

References 26 publications

Ribosomal scanning past the primary initiation codon as a mechanism for expression of CTL epitopes encoded in alternative reading frames.

Ribosomal scanning past the primary initiation codon as a mechanism for expression of CTL epitopes encoded in alternative reading frames.

Nowhere to hide: unconventional translation yields cryptic peptides for immune surveillance

Recognition of out‐of‐frame major histocompatibility complex class I‐restricted epitopes in vivo

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