Naturally Processed Non-canonical HLA-A*02:01 Presented Peptides

Hassan, Chopie; Chabrol, E; Jahn, Lorenz; Kester, Michel D.G.; Ru, Arnoud H. de; Drijfhout, Jan W.; Rossjohn, Jamie; Falkenburg, Frederick J H; Heemskerk, Mirjam H.M.; Gras, Stéphanie; Veelen, Peter A. van

doi:10.1074/jbc.m114.607028

Cited by 68 publications

(69 citation statements)

References 35 publications

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“…This MHC-peptidome study and others in viral infections (9,15,16) or in B cell lines (30,(42)(43)(44)(45) identified clusters of nested peptides. They include optimal epitopes as well as N-and/or Cextended peptides potentially presentable by several HLAs.…”

Section: Discussionsupporting

confidence: 51%

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

Ručević

Kourjian

Boucau

et al. 2016

J Virol

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H IV-specific T cells play an important role in the containment of infection as evidenced by the concurrent drop of viral load and the appearance of HIV-specific CD8 T cells in acute infection, T cell-driven immune pressure leading to predictable HLA-restricted HIV mutations, and the association between specific HLAs and epitopes or immune responses to specific proteins and spontaneous control of HIV. However, the lack of clear correlates of immune protection hampers efficient vaccine design (1).Screening and functional studies of T cells from HIV-infected persons or vaccinees use high nonphysiological concentrations of long HIV peptides exogenously pulsed onto cells or soluble major histocompatibility complex (MHC)-peptide multimers presenting peptides of optimal size (2, 3). These approaches bypass all steps required for intracellular antigen processing and presentation of HIV peptides by MHC class I (MHC-I) molecules (4). Determination of the amounts and sequences of peptides presented by an infected cell remains largely elusive despite the role of the peptides in immune recognition.Direct mass spectrometry (MS)-based sequencing has become a preferred and yet difficult approach for the unbiased identification and characterization of peptides naturally presented by MHC-I molecules displayed by healthy and cancerous cells or in the context of pathogen infection. However, considering the relatively low number of MHC-peptide complexes per cell and the

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Section: Discussionsupporting

confidence: 51%

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

Ručević

Kourjian

Boucau

et al. 2016

J Virol

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“…Previous studies focused on MHC class I-restricted epitopes documented antigenic peptides longer than the canonical 8 -9-mers presented onto MHC class I complexes and able to elicit CD8 ϩ T cell response (33)(34)(35)(36). Thus, the N-terminally extended peptides of the epitopes wt gp100 209 -217 and mut gp100 209 -217 may not only be precursors of the 9-mer epitopes but also exhibit sufficient affinity by themselves to bind the HLA-A*02:01 complex.…”

Section: A Single Thr/met Substitution In the Polypeptide Gp100mentioning

confidence: 99%

The T210M Substitution in the HLA-a*02:01 gp100 Epitope Strongly Affects Overall Proteasomal Cleavage Site Usage and Antigen Processing

Textoris-Taube

Keller

Liepe

et al. 2015

Journal of Biological Chemistry

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MHC class I-restricted epitopes, which carry a tumor-specific mutation resulting in improved MHC binding affinity, are preferred T cell receptor targets in innovative adoptive T cell therapies. However, T cell therapy requires efficient generation of the selected epitope. How such mutations may affect proteasome-mediated antigen processing has so far not been studied. Therefore, we analyzed by in vitro experiments the effect on antigen processing and recognition of a T210M exchange, which previously had been introduced into the melanoma gp100 209 Protein degradation by the ubiquitin-proteasome system plays an important role in regulating cellular protein homeostasis. Concomitant with the degradation of proteins, the 20S proteasome, which is the catalytic core of the ubiquitin-proteasome system, generates peptides of 8 -12 amino acids in length or N-terminally extended precursor peptides that, after trimming by endoplasmic reticulum (ER) 3 resident amino peptidases (ERAPs), can bind MHC class I molecules in the ER to be presented at the cell surface to CD8 ϩ T cells for immune recognition. These antigenic peptides can be produced by the proteasome by normal peptide-bond hydrolysis or by proteasomecatalyzed peptide splicing. The latter reaction generates peptides that have a different sequence than the original antigen, and it can occur by binding fragments of a single molecule (cis proteasome-catalyzed peptide splicing) or of two distinct molecules (trans proteasome-catalyzed peptide splicing) (1-4).In vitro experiments performed with purified 20S proteasomes were shown to closely reflect the in vivo situation, making it an ideal platform to study the generation of non-spliced and spliced antigenic peptides in vitro (1,(5)(6)(7)(8)(9)(10)(11). Under ideal conditions the 20S proteasome exists in two isoforms, i.e. the standard 20S proteasome (s-proteasomes) with the active site subunits ␤1, ␤2, and ␤5 and the 20S immunoproteasomes (i-proteasomes) with the inducible active site subunits ␤1i, ␤2i, and ␤5i. Constitutive expression of true i-proteasomes appears to be restricted to a small number of mainly immune cells like B or T cells. In contrast, the expression of so-called intermediatetype proteasomes containing both standard-and immuno-active subunits appears to be more frequent. Intermediate-type proteasomes are expressed in most tumor cells and in many tissues of the human body under normal physiological nutrition and growth conditions (12). It has been recently shown that the active subunit composition of 20S proteasomes in principle does not affect the quality of proteasome-generated peptides (5,13,14). Nevertheless, proteasomal subunit composition can strongly affect cleavage site usage within a given substrate and hence the relative quantity of non-spliced or spliced peptides produced. Such quantitative differences in the generation of cleavage products can strongly affect cell surface presentation

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“…Traditionally, there has been a focus on 9mer peptides when mapping HLA-I restricted T cell epitopes, but peptides of other lengths can bind HLA-I molecules (13) and elicit immune responses as evidenced by multiple dominant epitopes of length 8, 10 and 11 (14–17), and occasionally much longer peptides up to length 15 (17–19). MHC binding predictions for peptides of non-canonical lengths are available, but in many cases their predictions are extrapolated from 9mer data (20) and will predict a roughly similar affinity range for peptides of any given length.…”

Section: Introductionmentioning

confidence: 99%

The Length Distribution of Class I–Restricted T Cell Epitopes Is Determined by Both Peptide Supply and MHC Allele–Specific Binding Preference

Trolle

McMurtrey

Sidney

et al. 2016

The Journal of Immunology

190

196

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HLA class I binding predictions are widely used to identify candidate peptide targets of human CD8+ T cell responses. Many such approaches focus exclusively on a limited range of peptide lengths, typically 9 and sometimes 9-10 amino acids, despite multiple examples of dominant epitopes of other lengths. Here, we examined if epitope predictions can be improved by incorporating the natural length distribution of HLA class I ligands. We found that while different HLA alleles have diverse length binding preferences, the length profiles of ligands that are naturally presented by these alleles are much more homogeneous. We hypothesized that this is due to a defined length profile of peptides available for HLA binding in the endoplasmic reticulum. Based on this, we created a model of HLA allele specific ligand length profiles, and demonstrate how this model, in combination with HLA binding predictions, greatly improves comprehensive identification of CD8+ T cell epitopes.

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Naturally Processed Non-canonical HLA-A*02:01 Presented Peptides

Cited by 68 publications

References 35 publications

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses

The T210M Substitution in the HLA-a*02:01 gp100 Epitope Strongly Affects Overall Proteasomal Cleavage Site Usage and Antigen Processing

The Length Distribution of Class I–Restricted T Cell Epitopes Is Determined by Both Peptide Supply and MHC Allele–Specific Binding Preference

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