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Tina Heyder, Maxie Kohler, Nataliya K Tarasova, Sabrina Haag, Dorothea Rutishauser, Natalia V Rivera, Charlotta Sandin, Sohel Mia, Vivianne Malmström, Åsa M Wheelock, Jan Wahlström, Rikard Holmdahl, Anders Eklund, Roman A Zubarev, Johan Grunewald, A Jimmy Ytterberg
Immune-mediated diseases strongly associating with human leukocyte antigen (HLA) alleles are likely linked to specific antigens. These antigens are presented to T cells in the form of peptides bound to HLA molecules on antigen presenting cells, e.g. dendritic cells, macrophages or B cells. The identification of HLA-DR-bound peptides presents a valuable tool to investigate the human immunopeptidome. The lung is likely a key player in the activation of potentially auto-aggressive T cells prior to entering target tissues and inducing autoimmune disease...
September 2016: Molecular & Cellular Proteomics: MCP
Markus W Löffler, P Anoop Chandran, Karoline Laske, Christopher Schroeder, Irina Bonzheim, Mathias Walzer, Franz J Hilke, Nico Trautwein, Daniel J Kowalewski, Heiko Schuster, Marc Günder, Viviana A Carcamo Yañez, Christopher Mohr, Marc Sturm, Huu-Phuc Nguyen, Olaf Riess, Peter Bauer, Sven Nahnsen, Silvio Nadalin, Derek Zieker, Jörg Glatzle, Karolin Thiel, Nicole Schneiderhan-Marra, Stephan Clasen, Hans Bösmüller, Falko Fend, Oliver Kohlbacher, Cécile Gouttefangeas, Stefan Stevanović, Alfred Königsrainer, Hans-Georg Rammensee
BACKGROUND & AIMS: We report a novel experimental immunotherapeutic approach in a patient with metastatic intrahepatic cholangiocarcinoma. In the 5year course of the disease, the initial tumor mass, two local recurrences and a lung metastasis were surgically removed. Lacking alternative treatment options, aiming at the induction of anti-tumor T cells responses, we initiated a personalized multi-peptide vaccination, based on in-depth analysis of tumor antigens (immunopeptidome) and sequencing...
October 2016: Journal of Hepatology
Michal Bassani-Sternberg, George Coukos
The antigenic landscape of tumors is distinct from healthy cells and has been the rationale behind a variety of vaccination trials. Typically the target tumor-associated antigens have been of self origin and have rarely induced effective anti-tumor responses. Recent data show that activation of the immune system by immune checkpoint blocking therapies leads to tumor rejection and that recognition of mutated antigens, known as 'neo-antigens' plays a key role. Discovery of neo-antigens relies mainly on prediction-based interrogation of the 'mutanome' using genomic information as input, followed by T-cell screening...
August 2016: Current Opinion in Immunology
Anthony W Purcell, Nathan P Croft, David C Tscharke
We review approaches to quantitate antigen presentation using a variety of biological and biochemical readouts and highlight the emerging role of mass spectrometry (MS) in defining and quantifying MHC-bound peptides presented at the cell surface. The combination of high mass accuracy in the determination of the molecular weight of the intact peptide of interest and its signature pattern of fragmentation during tandem MS provide an unambiguous and definitive identification. This is in contrast to the potential receptor cross-reactivity towards closely related peptides and variable dose responsiveness seen in biological readouts...
June 2016: Current Opinion in Immunology
Lawrence J Stern, Laura Santambrogio
Recent advances in mass spectrometry technology have facilitated detailed examination of MHC-II immunopeptidomes, for example the repertoires of peptides bound to MHC-II molecules expressed in antigen presenting cells. These studies have deepened our view of MHC-II presentation. Other studies have broadened our view of pathways leading up to peptide loading. Here we review these recent studies in the context of earlier work on conventional and non-conventional MHC-II processing. The message that emerges is that sources of antigen beyond conventional endosomal processing of endocytosed proteins are important for generation of cellular immune responses to pathogens and maintenance of central and peripheral tolerance...
June 2016: Current Opinion in Immunology
Pouya Faridi, Ruedi Aebersold, Etienne Caron
We present the first standardized HLA peptidomics dataset generated by the immunopeptidomics community. The dataset is composed of native HLA class I peptides as well as synthetic HLA class II peptides that were acquired in data-dependent acquisition mode using multiple types of mass spectrometers. All laboratories used the spiked-in landmark iRT peptides for retention time normalization and data analysis. The mass spectrometric data were deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD001872...
June 2016: Data in Brief
Etienne Caron, Daniel J Kowalewski, Ching Chiek Koh, Theo Sturm, Heiko Schuster, Ruedi Aebersold
The myriad of peptides presented at the cell surface by class I and class II major histocompatibility complex (MHC) molecules are referred to as the immunopeptidome and are of great importance for basic and translational science. For basic science, the immunopeptidome is a critical component for understanding the immune system; for translational science, exact knowledge of the immunopeptidome can directly fuel and guide the development of next-generation vaccines and immunotherapies against autoimmunity, infectious diseases, and cancers...
December 2015: Molecular & Cellular Proteomics: MCP
Robin B Hartholt, Ivan Peyron, Jan Voorberg
Major histocompatibility complex class II (MHCII)-restricted peptide presentation is crucial for the selection and subsequent proliferation of antigen specific CD4+ T cells. While selection of antigen-specific CD4+ T cells is beneficial in the context of vaccination, emergence of antigen CD4+ T cells following administration of therapeutic proteins like factor VIII (FVIII) is not desirable. The mechanism of uptake, processing and presentation of FVIII by antigen-presenting cells (APCs) has been the subject of intense study over the past 10 years...
March 2016: Cellular Immunology
Nicola Ternette, Hongbing Yang, Thomas Partridge, Anuska Llano, Samandhy Cedeño, Roman Fischer, Philip D Charles, Nadine L Dudek, Beatriz Mothe, Manuel Crespo, William M Fischer, Bette T M Korber, Morten Nielsen, Persephone Borrow, Anthony W Purcell, Christian Brander, Lucy Dorrell, Benedikt M Kessler, Tomáš Hanke
Recognition and eradication of infected cells by cytotoxic T lymphocytes is a key defense mechanism against intracellular pathogens. High-throughput definition of HLA class I-associated immunopeptidomes by mass spectrometry is an increasingly important analytical tool to advance our understanding of the induction of T-cell responses against pathogens such as HIV-1. We utilized a liquid chromatography tandem mass spectrometry workflow including de novo-assisted database searching to define the HLA class I-associated immunopeptidome of HIV-1-infected human cells...
January 2016: European Journal of Immunology
Ingrid M M Schellens, Ilka Hoof, Hugo D Meiring, Sanne N M Spijkers, Martien C M Poelen, Jacqueline A M van Gaans-van den Brink, Kees van der Poel, Ana I Costa, Cecile A C M van Els, Debbie van Baarle, Can Kesmir
The cytotoxic T cell (CTL) response is determined by the peptide repertoire presented by the HLA class I molecules of an individual. We performed an in-depth analysis of the peptide repertoire presented by a broad panel of common HLA class I molecules on four B lymphoblastoid cell-lines (BLCL). Peptide elution and mass spectrometry analysis were utilised to investigate the number and abundance of self-peptides. Altogether, 7897 unique self-peptides, derived of 4344 proteins, were eluted. After viral infection, the number of unique self-peptides eluted significantly decreased compared to uninfected cells, paralleled by a decrease in the number of source proteins...
2015: PloS One
Anastasia Mpakali, Emmanuel Saridakis, Karl Harlos, Yuguang Zhao, Athanasios Papakyriakou, Paraskevi Kokkala, Dimitris Georgiadis, Efstratios Stratikos
Aminopeptidases that generate antigenic peptides influence immunodominance and adaptive cytotoxic immune responses. The mechanisms that allow these enzymes to efficiently process a vast number of different long peptide substrates are poorly understood. In this work, we report the structure of insulin-regulated aminopeptidase, an enzyme that prepares antigenic epitopes for cross-presentation in dendritic cells, in complex with an antigenic peptide precursor analog. Insulin-regulated aminopeptidase is found in a semiclosed conformation with an extended internal cavity with limited access to the solvent...
September 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Etienne Caron, Lucia Espona, Daniel J Kowalewski, Heiko Schuster, Nicola Ternette, Adán Alpízar, Ralf B Schittenhelm, Sri H Ramarathinam, Cecilia S Lindestam Arlehamn, Ching Chiek Koh, Ludovic C Gillet, Armin Rabsteyn, Pedro Navarro, Sangtae Kim, Henry Lam, Theo Sturm, Miguel Marcilla, Alessandro Sette, David S Campbell, Eric W Deutsch, Robert L Moritz, Anthony W Purcell, Hans-Georg Rammensee, Stefan Stevanovic, Ruedi Aebersold
We present a novel mass spectrometry-based high-throughput workflow and an open-source computational and data resource to reproducibly identify and quantify HLA-associated peptides. Collectively, the resources support the generation of HLA allele-specific peptide assay libraries consisting of consensus fragment ion spectra, and the analysis of quantitative digital maps of HLA peptidomes generated from a range of biological sources by SWATH mass spectrometry (MS). This study represents the first community-based effort to develop a robust platform for the reproducible and quantitative measurement of the entire repertoire of peptides presented by HLA molecules, an essential step towards the design of efficient immunotherapies...
2015: ELife
Nicola Ternette, Peter D Block, Álvaro Sánchez-Bernabéu, Nicola Borthwick, Elisa Pappalardo, Sultan Abdul-Jawad, Beatrice Ondondo, Philip D Charles, Lucy Dorrell, Benedikt M Kessler, Tomáš Hanke
UNLABELLED: Cytotoxic T cells substantially contribute to the control of intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). Here, we evaluated the immunopeptidome of Jurkat cells infected with the vaccine candidate MVA.HIVconsv, which delivers HIV-1 conserved antigenic regions by using modified vaccinia virus Ankara (MVA). We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify 6,358 unique peptides associated with the class I human leukocyte antigen (HLA), of which 98 peptides were derived from the MVA vector and 7 were derived from the HIVconsv immunogen...
June 2015: Journal of Virology
Efstratios Stratikos, Athanasios Stamogiannos, Efthalia Zervoudi, Doriana Fruci
Endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1 and ERAP2) are key components on the pathway that generates antigenic epitopes for presentation to cytotoxic T-lymphocytes (CTLs). Coding single nucleotide polymorphisms (SNPs) in these enzymes have been associated with pre-disposition to several major human diseases including inflammatory diseases with autoimmune etiology, viral infections, and virally induced cancer. The function of these enzymes has been demonstrated to affect CTL and natural killer cell responses toward healthy and malignant cells as well as the production of inflammatory cytokines...
2014: Frontiers in Oncology
Diana P Granados, Céline M Laumont, Pierre Thibault, Claude Perreault
T-cell development and function are regulated by MHC-associated self peptides, collectively referred to as the immunopeptidome. Large-scale mass spectrometry studies have highlighted three key features of the immunopeptidome. First, it is not a mirror of the proteome or the transcriptome, and its content cannot be predicted with currently available bioinformatic tools. Second, the immunopeptidome is more plastic than previously anticipated, and is molded by several cell-intrinsic and cell-extrinsic factors...
June 2015: Current Opinion in Immunology
Jonathan A Trujillo, Nathan P Croft, Nadine L Dudek, Rudragouda Channappanavar, Alex Theodossis, Andrew I Webb, Michelle A Dunstone, Patricia T Illing, Noah S Butler, Craig Fett, David C Tscharke, Jamie Rossjohn, Stanley Perlman, Anthony W Purcell
Cysteine-containing peptides represent an important class of T cell epitopes, yet their prevalence remains underestimated. We have established and interrogated a database of around 70,000 naturally processed MHC-bound peptides and demonstrate that cysteine-containing peptides are presented on the surface of cells in an MHC allomorph-dependent manner and comprise on average 5-10% of the immunopeptidome. A significant proportion of these peptides are oxidatively modified, most commonly through covalent linkage with the antioxidant glutathione...
October 3, 2014: Journal of Biological Chemistry
R Klar, S Schober, M Rami, S Mall, J Merl, S M Hauck, M Ueffing, A Admon, J Slotta-Huspenina, M Schwaiger, S Stevanović, R A J Oostendorp, D H Busch, C Peschel, A M Krackhardt
T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting...
December 2014: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Nadine L Dudek, Anthony W Purcell
Type 1 diabetes results from the autoimmune-mediated destruction of insulin-secreting beta cells, leading to beta cell loss and insulin deficiency. Presentation of peptides derived from beta cell proteins to autoreactive lymphocytes is critical for the development of disease, and the list of antigens recognized is increasing. A number of these proteins are found within the beta cell secretory granules, which are transiently exposed to the immune system during normal cellular function. How the interplay of environmental and genetic determinants culminates in destructive autoimmunity remains to be clearly defined...
2014: Vitamins and Hormones
Shraddha Kumari, Sébastien Wälchli, Lars-Egil Fallang, Weiwen Yang, Fridtjof Lund-Johansen, Ton N Schumacher, Johanna Olweus
HLA molecules presenting peptides derived from tumor-associated self-antigens (self-TAA) are attractive targets for T-cell-based immunotherapy of cancer. However, detection of such epitopes is hampered by self-tolerance and limitations in the sensitivity of mass spectrometry. Here, we used T cells from HLA-A2-negative donors as tools to detect HLA-A2-bound peptides from two leukemia-associated differentiation antigens; CD20 and the previously undescribed cancer target myeloperoxidase. A high-throughput platform for epitope discovery was designed using dendritic cells cotransfected with full-length transcripts of self-TAA and HLA-A2 to allow presentation of all naturally processed peptides from a predefined self-protein on foreign HLA...
January 7, 2014: Proceedings of the National Academy of Sciences of the United States of America
Nadine L Dudek, Chor Teck Tan, Dhana G Gorasia, Nathan P Croft, Patricia T Illing, Anthony W Purcell
Type 1 diabetes is characterized by the autoimmune destruction of pancreatic β-cells. Recognition of major histocompatibility complex (MHC)-bound peptides is critical for both the initiation and progression of disease. In this study, MHC peptide complexes were purified from NIT-1 β-cells, interferon-γ (IFN-γ)-treated NIT-1 cells, splenic and thymic tissue of 12-week-old NOD mice, and peptides identified by mass spectrometry. In addition to global liquid chromatography-tandem mass spectrometry analysis, the targeted approach of multiple-reaction monitoring was used to quantitate the immunodominant K(d)-restricted T-cell epitope islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)₂₀₆₋₂₁₄...
November 2012: Diabetes
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