All the peptides that fit: the beginning, the middle, and the end of the MHC class I antigen‐processing pathway

Shastri, Nilabh; Cardinaud, Sylvain; Schwab, Susan R.; Serwold, Thomas; Kunisawa, Jun

doi:10.1111/j.0105-2896.2005.00321.x

Cited by 120 publications

(105 citation statements)

References 101 publications

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“…The total pool of cytosolic peptides formed by proteolysis is very diverse and estimated to be composed by millions of peptides [2,3,[46][47][48]. From this pool, only a small repertoire is selected for presentation by MHC-I molecules at the surfaces of cells.…”

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 production of short peptides (8 -12 aa) presented by HLA class I molecules, called CTL epitopes when recognized by CD8 + cytotoxic T lymphocytes (CTLs), occurs in the cytosol during the continuous turnover of full-length and misfolded proteins into peptides and eventually free amino acids [1][2][3] . This cleavage process is accomplished by the multicatalytic proteasome complex and cytosolic peptidases 1,3 .…”

Section: Introductionmentioning

confidence: 99%

“…The absence of C-terminal excision of CTL epitopes in proteasome-inhibited cells [8][9][10] , together with failure to detect C-terminal trimming activities in the cytosol or ER, has led to the current notion that solely the proteasome liberates the exact C-terminus 1,2 . Cytosolic endopeptidases, however, may also produce peptides with a C-terminus fit for class I binding from protein degradation products lacking such an anchor.…”

Section: Introductionmentioning

confidence: 99%

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

et al. 2010

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Cytoxic T lymphocytes (CTLs) recognize peptides presented by HLA class I molecules on the cell surface. The C-terminus of these CTL epitopes is predominantly generated by the proteasome.Here we demonstrate that the cytosolic endopeptidases nardilysin and thimet oligopeptidase (TOP) complemented proteasome activity. Nardilysin and TOP were required, either together or alone, for the generation of a tumor-specific CTL epitope from PRAME, an immunodominant CTL epitope from Epstein-Barr virus, and a clinically important epitope from melanoma-protein MART-1. TOP functioned as C-terminal trimming peptidase in antigen processing and nardilysin contributed to both C-terminal and N-terminal CTL epitope generation. By broadening the antigenic peptide repertoire, nardilysin and TOP strengthen the immune defense against intracellular pathogens and cancer.

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“…8 Multiple protein interactions are required for efficient assembly of MHC class I heavy chain and b2 microglobulin (b2m) with endogenous peptides. 9 Peptide processing and transport into the endoplasmic reticulum involves the transporters associated with antigen processing, (TAP-1 and TAP-2), and the proteasome complex, which also includes the MHC-encoded low-molecular-weight proteins LMP-2 and LMP-7. 9 Loss of expression or downregulation of any of these proteins has been described.…”

mentioning

confidence: 99%

“…9 Peptide processing and transport into the endoplasmic reticulum involves the transporters associated with antigen processing, (TAP-1 and TAP-2), and the proteasome complex, which also includes the MHC-encoded low-molecular-weight proteins LMP-2 and LMP-7. 9 Loss of expression or downregulation of any of these proteins has been described. Total loss of HLA class I expression has been observed in tumor cells, [10][11][12] as well as a selective loss of individual HLA alleles.…”

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confidence: 99%

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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All the peptides that fit: the beginning, the middle, and the end of the MHC class I antigen‐processing pathway

Cited by 120 publications

References 101 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

Antigen processing by nardilysin and thimet oligopeptidase generates cytotoxic T cell epitopes

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

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