An essential role for tripeptidyl peptidase in the generation of an MHC class I epitope

Seifert, Ulrike; Marañón, Concepción; Shmueli, Ayelet; Desoutter, Jean-François; Wesoloski, Lisa M.; Janek, Katharina; Henklein, Peter; Diescher, Susanne; Andrieu, Muriel; Weinschenk, Toni; Schild, Hansjoerg; Laderach, Diego J.; Galy, Anne; Haas, Gaby; Kloetzel, Peter‐M.; Reiss, Yuval; Hosmalin, Anne

doi:10.1038/ni905

Cited by 210 publications

(176 citation statements)

References 37 publications

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“…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 their cooperation with the proteasome have not been fully characterized.…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…In most cases, the proteasome produces peptides with correct C-termini for HLA class I epitopes (Cascio et al 2001). However, the generation of correct Ctermini has also been attributed to tripeptidyl peptidase II (TPPII) which has been shown to be essential for producing particular epitopes (Geier et al 1999;Seifert et al 2003). Peptides from the cytosol are transported by the transporter associated with antigen processing (TAP) to the endoplasmic reticulum (ER) (Kleijmeer et al 1992) where their Ntermini are specifically trimmed, in the final step of antigen generation, to a particular size of eight or nine residues by ER-associated aminopeptidases (Saveanu et al 2005;York et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Stocki

Morris

Preisinger

et al. 2010

Cell Stress and Chaperones

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Heat shock protein 70 (HSPA) is a molecular chaperone which has been suggested to shuttle human leukocyte antigen (HLA) epitope precursors from the proteasome to the transporter associated with antigen processing. Despite the reported observations that peptides chaperoned by HSPA are an effective source of antigens for cross-priming, little is known about the peptides involved in the process. In this study, we investigated the possible involvement of HSPA in HLA class I or class II antigen presentation and analysed the antigenic potential of the associated peptides. HSPA was purified from CCRF-CEM and K562 cell lines, and using mass spectrometry techniques, we identified 44 different peptides which were copurified with HSPA. The affinity of the identified peptides to two HSPA isoforms, HSPA1A and HSPA8, was confirmed using a peptide array. Four of the HSPAassociated peptides were matched with 13 previously reported HLA epitopes. Of these 13 peptides, nine were HLA class I and four were HLA class II epitopes. These results demonstrate the association of HSPA with HLA class I and class II epitopes, therefore providing further evidence for the involvement of HSPA in the antigen presentation process.

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“…39 Alternative cytosolic pathways have also been reported and the processing proteases in these cases can be cysteine proteases 40 or tripeptidyl peptidase II. 41,42 Translocation of peptides into the ER is provided by transporters associated with antigen processing (TAP), but in some cases may also be TAP-independent, carried out by the sec61 translocon or by undefined mechanisms. 43 The exact pathway, which is involved in processing the epitope SSX2 103-111 has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…We used several antigen presenting cells to demonstrate that the Fab-VIE1 could bind to the specific MHC-peptide complex not only in its recombinant soluble form, but also in the native form expressed on the cell surface. Soluble Fab-VIE1 reacted with SSX2 103-111 peptide loaded T2 cells and HLA-A*0201 1 EBV-transformed lymphoblastoid cell line, but not with cells loaded with one of 6 different HLA-A*0201-binding peptides, SSX2 [41][42][43][44][45][46][47][48][49] , NY-ESO-1 157-165 , influenza matrix protein 58-66 , gp100 209-217 , Melan-A [26][27][28][29][30][31][32][33][34][35] and Carboanhydrase-IV 254-262 , respectively. No binding of Fab-VIE1 to the HLA-A*0201 2 EBV-transformed B-lymphocytes was observed, neither when pulsed with the SSX2 103-111 peptide nor with control peptides (Fig.…”

Section: Characterization Of Fab-vie1 With Specificity For Ssx2 103-1mentioning

confidence: 96%

“…Specificity of selected Fab-VIE1 was demonstrated. In ELISA Fab-VIE1 reacted specifically with the SSX2 103-111 containing HLA-A*0201 complex, but not with 4 control complexes, containing HLA-A*0201-restricted epitopes of Melan-A, CMV pp65, NY-ESO-1 and SSX2 [41][42][43][44][45][46][47][48][49] respectively. Importantly, cross-reactivity to SSX2 41-49 / HLA-A*0201 complex could be excluded (Fig.…”

Section: Characterization Of Fab-vie1 With Specificity For Ssx2 103-1mentioning

confidence: 99%

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Differential presentation of tumor antigen‐derived epitopes by MHC‐class I and antigen‐positive tumor cells

Held

Neumann

Sturm

et al. 2008

Intl Journal of Cancer

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SSX2 is a member of the family of cancer/testis antigens. The SSX2 derived peptide SSX2 [103][104][105][106][107][108][109][110][111] has been shown to be presented to cytotoxic T-lymphocytes (CTL) by Major-Histocompatibility (MHC) Class-I complexes after endogenous processing, more precisely by the allele HLA-A*0201. The HLA-A*0201-and SSX2-positive melanoma cell line SK-Mel-37 but not Me275 had been shown to elicit reactivity in SSX2 103-111 specific cytotoxic T-lymphocytes. To analyze the correlation between SSX2 103-111 presentation and T-cell stimulation, we intended to visualize presentation of SSX2 103-111 in these melanoma cell lines. Fab-antibodies were established from a human phage library with specificity for SSX2 103-111 /HLA-A*0201 complexes (but non-reactive with HLA-A*0201 or SSX2 103-111 alone) and used to visualize the presentation of SSX2 [103][104][105][106][107][108][109][110][111]

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An essential role for tripeptidyl peptidase in the generation of an MHC class I epitope

Cited by 210 publications

References 37 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

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Differential presentation of tumor antigen‐derived epitopes by MHC‐class I and antigen‐positive tumor cells

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