The Varicellovirus-Encoded TAP Inhibitor UL49.5 Regulates the Presentation of CTL Epitopes by Qa-1b1

Hall, Thorbald van; Laban, Sandra; Koppers-Lalić, Danijela; Koch, Joachim; Precup, Calin Gheorghe; Asmawidjaja, Patrick S.; Offringa, Rienk; Wiertz, Emmanuel J. H. J.

doi:10.4049/jimmunol.178.2.657

Cited by 36 publications

(38 citation statements)

References 59 publications

(60 reference statements)

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“…The studied Trh4 peptide represents a much broader repertoire of TAP-independent peptides, as we have shown that TAP-deficient cells are recognized by a diverse pool of CTL clones with distinct MHC restriction patterns [36,41]. Interestingly, the non-classical MHC molecule Qa-1 b seems to play a dominant role in the presentation of these TAP-independent antigens [49][50][51]. Recently, we showed the existence of the human equivalent of this novel CTL category [52,53].…”

Section: Discussionmentioning

confidence: 98%

“…Cell variants over-expressing H-2D b or Trh4 (accession number UniProtKB/Swiss-Prot Q9D6K9 LASS5_MOUSE) were generated by retroviral gene transfer using the LZRS vector containing GFP behind an internal ribosome entry site [50]. RMA.Trh4 cells were differentially sorted according to GFP levels to generate variants with low, intermediate and high expression of Trh4.…”

Section: Cell Lines and Micementioning

confidence: 99%

“…UL49.5 is a gene from the Bovine Herpes Virus-1 and blocks mouse TAP activity [40,50]. Generation and culture of T-cell clones was described previously [45,36,50]. CD8 1 T-cell clones used in this study: Qa-1-resticted CTL B12i is specific for the TAPdependent peptide Qdm (AMAPTRLLL); H-2D b -restricted CTL clone 1 is specific for the TAP-dependent MuLV gag-leader peptide (CCLCLTVFL); H-2D b -restricted CTL clone B5 is specific for the TAP-independent Trh4 peptide (MCLRMTAVM).…”

Section: Cell Lines and Micementioning

confidence: 99%

“…MCA.TAP1 is a variant of MCA fibrosarcoma where the mouse TAP1 gene was introduced. UL49.5 is a gene from the Bovine Herpes Virus-1 and blocks mouse TAP activity [40,50]. Generation and culture of T-cell clones was described previously [45,36,50].…”

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Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

et al. 2011

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We recently described a category of TAP-independent peptide-epitopes that are selectively presented by cells with processing defects in the classical MHC class I (MHC-I) pathway. Here, we studied the ER-resident ceramide synthase Trh4 as a prototypic example of these neo-antigens and found that moderate inhibition of TAP permits cell surface presentation of the Trh4 peptide. The absence of this peptide from WT cells was not related to the binding or stability of the Trh4/D b complexes, or to the availability of MHC-I heavy chains, but rather to the limited expression of the antigen. Strongly elevated antigen levels were needed to reach comparable peptide display on WT as on TAP-deficient cells. Our data suggest that the normal influx of TAP-transported peptides in the ER during routine processing creates an efficient barrier for peptides from alternative processing routes. Impairment of TAP function, as commonly found in cancers and virus-infected cells, lowers this resistance allowing for MHC-I presentation of other peptide sources.Key words: Antigen processing . Cytotoxic T lymphocytes . Transporter associated with peptide processing Supporting Information available online IntroductionCytotoxic T lymphocytes (CTLs) are key effector cells of the adaptive immune system and circulate throughout the body in search of their cognate peptides that are presented by MHC class I (MHC-I) molecules. T-cell receptors determine the antigen specificity of CTLs and engagement with peptide/MHC-I complexes leads to their activation and elimination of target cells. Therefore, the process of MHC-I antigen processing and presentation, which operates in all nucleated cells of our body, is crucial for CTL immune surveillance [1][2][3]. The highly complex repertoire of MHC-I presented peptides reflects the total proteome of cells and derives from the physiological turnover of proteins, a process that is largely operated by the multicatalytic enzyme proteasome [4,5]. In addition to the proteasome, other proteolytic enzymes in the cytosol have been implicated in the liberation of peptides for MHC-I presentation, some of which can compensate for the lack of proteasome activity [1,6,7]. For instance, tripeptidyl peptidase II (TPPII), insulin-degrading enzyme (IDE), thimet oligopeptidase (TOP) and nardilysin have been implicated in the generation of some CTL epitopes [8][9][10]. However, the relative contributions of these novel peptidases and Ã These authors contributed equally to this work 3114their cooperation with the proteasome have not been fully characterized.The intermediate peptide products are rescued from total breakdown by these cytosolic proteases through translocation into the ER. Subsequently, peptides are trimmed and loaded into the grooves of MHC-I molecules, a dynamic process that is mediated by the peptide loading complex (PLC) consisting of MHC-I, b2m, ERp57, TAP, tapasin and chaperones [11][12][13]. The TAP peptide transport is operated by the heterodimer pump TAP1/TAP2, members of the ABC transporter family. The imp...

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Section: Discussionmentioning

confidence: 98%

Section: Cell Lines and Micementioning

confidence: 99%

Section: Cell Lines and Micementioning

confidence: 99%

mentioning

confidence: 99%

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Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

et al. 2011

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“…The UL49.5 protein is able to prevent peptide transport by murine TAP as well as huTAP (38,60). Therefore, it is likely that UL49.5 can also block rat TAP.…”

Section: Ul495 Efficiently Interacts With Rat Tap and Inhibits Peptimentioning

confidence: 99%

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

Verweij

Koppers-Lalić

Loch

et al. 2008

The Journal of Immunology

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TAP translocates virus-derived peptides from the cytosol into the endoplasmic reticulum, where the peptides are loaded onto MHC class I molecules. This process is crucial for the detection of virus-infected cells by CTL that recognize the MHC class I-peptide complexes at the cell surface. The varicellovirus bovine herpesvirus 1 encodes a protein, UL49.5, that acts as a potent inhibitor of TAP. UL49.5 acts in two ways, as follows: 1) by blocking conformational changes of TAP required for the translocation of peptides into the endoplasmic reticulum, and 2) by targeting TAP1 and TAP2 for proteasomal degradation. At present, it is unknown whether UL49.5 interacts with TAP1, TAP2, or both. The contribution of other members of the peptide-loading complex has not been established. Using TAP-deficient cells reconstituted with wild-type and recombinant forms of TAP1 and TAP2, TAP was defined as the prime target of UL49.5 within the peptide-loading complex. The presence of TAP1 and TAP2 was required for efficient interaction with UL49.5. Using deletion mutants of TAP1 and TAP2, the 6+6 transmembrane core complex of TAP was shown to be sufficient for UL49.5 to interact with TAP and block its function. However, UL49.5-induced inhibition of peptide transport was most efficient in cells expressing full-length TAP1 and TAP2. Inhibition of TAP by UL49.5 appeared to be independent of the presence of other peptide-loading complex components, including tapasin. These results demonstrate that UL49.5 acts directly on the 6+6 transmembrane TAP core complex of TAP by blocking essential conformational transitions required for peptide transport.

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Insights into the processing of MHC class I ligands gained from the study of human tumor epitopes

Vigneron

Eynde

2011

Cell. Mol. Life Sci.

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The molecular definition of tumor antigens recognized by cytolytic T lymphocytes (CTL) started in the late 1980s, at a time when the MHC class I antigen processing field was in its infancy. Born together, these two fields of science evolved together and provided each other with critical insights. Over the years, stimulated by the potential interest of tumor antigens for cancer immunotherapy, scientists have identified and characterized numerous antigens recognized by CTL on human tumors. These studies have provided a wealth of information relevant to the mode of production of antigenic peptides presented by MHC class I molecules. A number of tumor antigenic peptides were found to result from unusual mechanisms occurring at the level of transcription, translation or processing. Although many of these mechanisms occur in the cell at very low level, they are relevant to the immune system as they determine the killing of tumor cells by CTL, which are sensitive to low levels of peptide/MHC complexes. Moreover, these unusual mechanisms were found to occur not only in tumor cells but also in normal cells. Thereby, the study of tumor antigens has illuminated many aspects of MHC class I processing. We review here those insights into the MHC I antigen processing pathway that result from the characterization of human tumor antigens recognized by CTL.

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The Varicellovirus-Encoded TAP Inhibitor UL49.5 Regulates the Presentation of CTL Epitopes by Qa-1b1

Cited by 36 publications

References 59 publications

Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

Peptide transporter TAP mediates between competing antigen sources generating distinct surface MHC class I peptide repertoires

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

Insights into the processing of MHC class I ligands gained from the study of human tumor epitopes

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