Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

Durgeau, Aurélie; Hage, Faten El; Vergnon, Isabelle; Validire, Pierre; Montpréville, Vincent de; Besse, Benjamin; Soria, Jean‐Charles; Hall, Thorbald van; Mami‐Chouaib, Fathia

doi:10.4049/jimmunol.1102060

Cited by 38 publications

(46 citation statements)

References 47 publications

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“…These peptide sequences, called TEIPP (T-cell epitopes associated with impaired peptide processing), are not presented by normal cells and we can speculate, based on the results of the present study, that one mechanism governing the absence from normal cells is related to the low expression level of the cognate proteins. In a parallel study, a proteasome-and TAPindependent tumor antigen from the signal sequence of the preprocalcitonin protein (ppCT [16][17][18][19][20][21][22][23][24][25] ) was found to represent a human TEIPP, in that this HLA-A2 presented peptide was selectively presented by tumor cells with TAP deficiency [54]. This peptide is liberated in the ER lumen by sequential cleavage with SP and SPP [55] and is a clear example of the alternative TAP-independent peptide repertoire.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2011

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“…The ER-directing parts of these peptides end up in the lumen of the ER and can be loaded unto MHC-I molecules (24,25). An immunogenic human tumor Ag from the leader sequence of calcitonin is released by this means, and TAP is dispensable for its presentation on cancer cell lines (26,27).…”

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New Role of Signal Peptide Peptidase To Liberate C-Terminal Peptides for MHC Class I Presentation

Oliveira

Querido

Sluijter

et al. 2013

The Journal of Immunology

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The signal peptide peptidase (SPP) is an intramembrane cleaving aspartyl protease involved in release of leader peptide remnants from the endoplasmic reticulum membrane, hence its name. We now found a new activity of SPP that mediates liberation of C-terminal peptides. In our search for novel proteolytic enzymes involved in MHC class I (MHC-I) presentation, we found that SPP generates the C-terminal peptide-epitope of a ceramide synthase. The display of this immunogenic peptide–MHC-I complex at the cell surface was independent of conventional processing components like proteasome and peptide transporter TAP. Absence of TAP activity even increased the MHC-I presentation of this Ag. Mutagenesis studies revealed the crucial role of the C-terminal location of the epitope and “helix-breaking” residues in the transmembrane region just upstream of the peptide, indicating that SPP directly liberated the minimal 9-mer peptide. Moreover, silencing of SPP and its family member SPPL2a led to a general reduction of surface peptide–MHC-I complexes, underlining the involvement of these enzymes in Ag processing and presentation.

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“…However, absence of TAP blocks their influx into the ER and peptides derived from alternative sources take over the peptide repertoire. As these peptides are generally derived from proteasome-independent mechanisms, it is possible to identify epitopes that can have escaped central and peripheral tolerance (12,13). The identification of a novel category of TEIPPs that are selectively presented on TAP-deficient cells represents a significant advance in our search for novel cancer-specific targets.…”

Section: Discussionmentioning

confidence: 99%

“…Most of the hitherto identified immunogenic H-2D b and HLA-A2-restricted TEIPP-epitopes are derived from either protein signal sequences that are processed by signal peptidases in the ER or from transmembrane proteins residing in the ER (10,11,13,37,38). The Trh4 protein is such an ER membrane spanning protein of which the C terminus is loaded unto H-2D b in a peptide-transporter-independent way.…”

Section: Discussionmentioning

confidence: 99%

“…The induction of TEIPP-specific CTL responses resulted in selective eradication of TAP-deficient tumors in vivo (7,11), suggesting the possibility to combine a TEIPP-specific CTL repertoire with a conventional CD8 + CTL immunotherapy strategy to prevent tumor immune escape. It has been recently demonstrated that impairment of TAP function, as commonly found in cancers and virus-infected cells, lowers the otherwise naturally occurring resistance for peptides from alternative processing routes, allowing for MHC-I presentation of other peptide sources (12,13).…”

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The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer

Hafstrand

Doorduijn

Duru

et al. 2016

The Journal of Immunology

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MHC class I downregulation represents a significant challenge for successful T cell–based immunotherapy. T cell epitopes associated with impaired peptide processing (TEIPP) constitute a novel category of immunogenic Ags that are selectively presented on transporter associated with Ag processing–deficient cells. The TEIPP neoepitopes are CD8 T cell targets, derived from nonmutated self-proteins that might be exploited to prevent immune escape. In this study, the crystal structure of H-2Db in complex with the first identified TEIPP Ag (MCLRMTAVM) derived from the Trh4 protein has been determined to 2.25 Å resolution. In contrast to prototypic H-2Db peptides, Trh4 takes a noncanonical peptide-binding pattern with extensive sulfur–π interactions that contribute to the overall complex stability. Importantly, the noncanonical methionine at peptide position 5 acts as a main anchor, altering only the conformation of the H-2Db residues Y156 and H155 and thereby forming a unique MHC/peptide conformer that is essential for recognition by TEIPP-specific T cells. Substitution of peptide residues p2C and p5M to the conservative α-aminobutyric acid and norleucine, respectively, significantly reduced complex stability, without altering peptide conformation or T cell recognition. In contrast, substitution of p5M to a conventional asparagine abolished recognition by the H-2Db/Trh4-specific T cell clone LnB5. We anticipate that the H-2Db/Trh4 complex represents the first example, to our knowledge, of a broader repertoire of alternative MHC class I binders.

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Different Expression Levels of the TAP Peptide Transporter Lead to Recognition of Different Antigenic Peptides by Tumor-Specific CTL

Cited by 38 publications

References 47 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

New Role of Signal Peptide Peptidase To Liberate C-Terminal Peptides for MHC Class I Presentation

The MHC Class I Cancer-Associated Neoepitope Trh4 Linked with Impaired Peptide Processing Induces a Unique Noncanonical TCR Conformer

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