Abrogation of CTL Epitope Processing by Single Amino Acid Substitution Flanking the C-Terminal Proteasome Cleavage Site

Beekman, N. J. C. M.; Veelen, Peter A. van; Hall, Thorbald van; Neisig, Anne; Sijts, Alice J.A.M.; Camps, Marcel; Kloetzel, Peter‐M.; Neefjes, Jacques; Melief, Cornelis J.M.; Ossendorp, Ferry

doi:10.4049/jimmunol.164.4.1898

Cited by 87 publications

(78 citation statements)

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“…The cleavage occurs between the P1 and the P1 0 position (Berger and Schechter 1970). It has been suggested that the P1 position is the most important position determining cleavage (Altuvia and Margalit 2000;Cascio et al 2001), although the flanking region may also be important (Ossendorp et al 1996;Beekman et al 2000;Mo et al 2000). One way of analyzing such data is to calculate the information content at the cleavage site and in the region flanking the cleavage site.…”

Section: Resultsmentioning

confidence: 99%

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

et al. 2003

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Intracellular proteins are degraded largely by proteasomes. In cells stimulated with gamma interferon , the active proteasome subunits are replaced by "immuno" subunits that form immunoproteasomes. Phylogenetic analysis of the immunosubunits has revealed that they evolve faster than their constitutive counterparts. This suggests that the immunoproteasome has evolved a function that differs from that of the constitutive proteasome. Accumulating experimental degradation data demonstrate, indeed, that the specificity of the immunoproteasome and the constitutive proteasome differs. However, it has not yet been quantified how different the specificity of two forms of the proteasome are. The main question, which still lacks direct evidence, is whether the immunoproteasome generates more MHC ligands. Here we use bioinformatics tools to quantify these differences and show that the immunoproteasome is a more specific enzyme than the constitutive proteasome. Additionally, we predict the degradation of pathogen proteomes and find that the immunoproteasome generates peptides that are better ligands for MHC binding than peptides generated by the constitutive proteasome. Thus, our analysis provides evidence that the immunoproteasome has co-evolved with the major histocompatibility complex to optimize antigen presentation in vertebrate cells.

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Section: Resultsmentioning

confidence: 99%

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

et al. 2003

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“…20S proteasomes were purified from a Epstein-Barr virus (immuno proteasome) and a HeLa cell line (constitutive proteasome) as described (24). Low molecular mass polypeptide 2 (LMP2) and LMP7 contents were confirmed by 2D immunoblotting (data not shown).…”

Section: Transporter Associated With Antigen Presentation (Tap) Transmentioning

confidence: 99%

Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes

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et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Type 1 diabetes is a T cell-mediated autoimmune disease, and insulin is an important target of the autoimmune response associated with ␤ cell destruction. The mechanism of destruction is still unknown. Here, we provide evidence for CD8 T cell autoreactivity associated with recurrent autoimmunity and loss of ␤ cell function in type 1 diabetic islet transplant recipients. We first identified an insulin B chain peptide (insB10-18) with extraordinary binding affinity to HLA-A2(*0201) that is expressed by the majority of type 1 diabetes patients. We next demonstrated that this peptide is naturally processed by both constitutive and immuno proteasomes and translocated to the endoplasmic reticulum by the peptide transporter TAP1 to allow binding to HLA-A2 in the endoplasmic reticulum and cell surface presentation. Peripheral blood mononuclear cells from a healthy donor were primed in vitro with this peptide, and CD8 T cells were isolated that specifically recognize target cells expressing the insulin B chain peptide. HLA-A2 insB10-18 tetramer staining revealed a strong association between detection of autoreactive CD8 T cells and recurrent autoimmunity after islet transplantation and graft failure in type 1 diabetic patients. We demonstrate that CD8 T cell autoreactivity is associated with ␤ cell destruction in type 1 diabetes in humans.insulin ͉ islet transplantation ͉ cytotoxic T lymphocyte ͉ tetramer

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“…SVM-Models trained using sparse sequence representation were selected. (A) Predictive performance (R p ) of SVM-models with regard to the fragment size used for training (1)(2)(3)(4)(5)(6)(7)(8)(9). Only the largest R p value achieved by a specific model (indicated in the abscissa) at each fragment size is represented.…”

Section: Resultsmentioning

confidence: 99%

Quantitative modeling of peptide binding to TAP using support vector machine

et al. 2009

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The transport of peptides to the endoplasmic reticulum by the transporter associated with antigen processing (TAP) is a necessary step towards determining CD8 T cell epitopes. In this work, we have studied the predictive performance of support vector machine models trained on single residue positions and residue combinations drawn from a large dataset consisting of 613 nonamer peptides of known affinity to TAP. Predictive performance of these TAP affinity models was evaluated under 10‐fold cross‐validation experiments and measured using Pearson's correlation coefficients (Rp). Our results show that every peptide position (P1–P9) contributes to TAP binding (minimum Rp of 0.26 ± 0.11 was achieved by a model trained on the P6 residue), although the largest contributions to binding correspond to the C‐terminal end (Rp = 0.68 ± 0.06) and the P1 (Rp = 0.51 ± 0.09) and P2 (0.57 ± 0.08) residues of the peptide. Training the models on additional peptide residues generally improved their predictive performance and a maximum correlation (Rp = 0.89 ± 0.03) was achieved by a model trained on the full‐length sequences or a residue selection consisting of the first 5 N‐ and last 3 C‐terminal residues of the peptides included in the training set. A system for predicting the binding affinity of peptides to TAP using the methods described here is readily available for free public use at http://imed.med.ucm.es/Tools/tapreg/. Proteins 2010. © 2009 Wiley‐Liss, Inc.

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Abrogation of CTL Epitope Processing by Single Amino Acid Substitution Flanking the C-Terminal Proteasome Cleavage Site

Cited by 87 publications

References 50 publications

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

Autoreactive CD8 T cells associated with β cell destruction in type 1 diabetes

Quantitative modeling of peptide binding to TAP using support vector machine

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