High‐resolution analysis of the murine MHC class II immunopeptidome

Sofron, Adriana; Ritz, Danilo; Neri, Dario; Fugmann, Tim

doi:10.1002/eji.201545930

Cited by 48 publications

(54 citation statements)

References 39 publications

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“…These should more closely reflect the distribution of source proteins and in vivo peptide repertoire than do the cell lines studies described above. Sofron et al reported almost 3000 I-A d binding peptides from BALB/c spleen, and a similar number of I-A b -binding peptides from C57BL/6 spleen [6]. As in the cell line studies described above, and as described previously for I-A b from murine splenocytes [11], peptides bound to MHC II in vitro derive from proteins present throughout the cell.…”

Section: Presentation Of Endogenous and Exogenous Antigensmentioning

confidence: 86%

“…Bergseng et al characterized up to 7400 HLA-DQ-bound peptides from each of several EBV-transformed B-lymphoblastoid cell lines, and used these to define peptide binding motifs for three celiac disease-associated DQ allotypes [5]. Similarly Sofron et al identified over 1000 peptides from the murine A20 lymphoma line, helping to refine the I-A d motif [6]. In each of these studies, the majority of eluted peptides derived from endogenous proteins, with a substantial fraction (up to 20%) derived from exogenous proteins brought into the cell by endocytosis.…”

Section: Presentation Of Endogenous and Exogenous Antigensmentioning

confidence: 99%

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The melting pot of the MHC II peptidome

Stern

Santambrogio

2016

Current Opinion in Immunology

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Recent advances in mass spectrometry technology have facilitated detailed examination of MHC-II immunopeptidomes, i.e. 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. The multiplicity of pathways results in a broad MHC II immunopeptidome that conveys the sampled environment to patrolling T cells.

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Section: Presentation Of Endogenous and Exogenous Antigensmentioning

confidence: 86%

Section: Presentation Of Endogenous and Exogenous Antigensmentioning

confidence: 99%

The melting pot of the MHC II peptidome

Stern

Santambrogio

2016

Current Opinion in Immunology

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“…Moreover, the unbiased search by mass spectrometry analysis enables the detection of ligands derived from post‐translational modification, which might be missed by conventional epitope prediction . Other examples are spliced peptide variants and the so far less well described MHC II immunopeptidome, although these peptides are currently also often difficult to detect by MS. In addition, so‐called ‘hot spots’ of preferential proteasomal processing and presentation within highly expressed proteins may be identified by comparison of ligandomes derived from different samples and mapping of frequently detected regions in a protein sequence .…”

Section: Strategies For Tumour Antigen Identification On Melanomamentioning

confidence: 99%

Tools to define the melanoma‐associated immunopeptidome

Bräunlein

Krackhardt

2017

Immunology

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SummaryImmunotherapies have been traditionally applied in malignant melanoma, which represent one of the most immunogenic tumours. Recently, immune checkpoint modulation has shown high therapeutic efficacy and may provide long-term survival in a significant proportion of affected patients. T cells are the major players in tumour rejection and recognize tumour cells predominantly in an MHC-dependent way. The immunopeptidome comprises the peptide repertoire presented by MHC class I and II molecules on the surface of the body's cells including tumour cells. To understand characteristics of suitable rejection antigens as well as respective effective T-cell responses, determination of the immunopeptidome is of utmost importance. Suitable rejection antigens need to be further characterized and validated not only to systematically improve current therapeutic approaches, but also to develop individualized treatment options. In this review, we report on current tools to explore the immunopeptidome in human melanoma and discuss current understanding and future developments to specifically detect and select those antigens that may be most relevant and promising for effective tumour rejection.

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“…Recent advances in mass spectrometry have enabled large‐scale analyses of the collection of peptides naturally presented by MHC molecules in a particular cell line. These technologies have a tremendous potential as they can generate thousands of data points in a single experiment (see for instance refs ). However, since antigen‐presenting cells normally express multiple MHC isoforms, the MHC restriction of each ligand is generally not known and must be assigned, either with a predictor of binding to MHC or through unsupervised clustering .…”

Section: Discussionmentioning

confidence: 99%

Machine learning reveals a non‐canonical mode of peptide binding to MHC class II molecules

et al. 2017

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MHC class II molecules play a fundamental role in the cellular immune system: they load short peptide fragments derived from extracellular proteins and present them on the cell surface. It is currently thought that the peptide binds lying more or less flat in the MHC groove, with a fixed distance of nine amino acids between the first and last residue in contact with the MHCII. While confirming that the great majority of peptides bind to the MHC using this canonical mode, we report evidence for an alternative, less common mode of interaction. A fraction of observed ligands were shown to have an unconventional spacing of the anchor residues that directly interact with the MHC, which could only be accommodated to the canonical MHC motif either by imposing a more stretched out peptide backbone (an 8mer core) or by the peptide bulging out of the MHC groove (a 10mer core). We estimated that on average 2% of peptides bind with a core deletion, and 0·45% with a core insertion, but the frequency of such non-canonical cores was as high as 10% for certain MHCII molecules. A mutational analysis and experimental validation of a number of these anomalous ligands demonstrated that they could only fit to their MHC binding motif with a non-canonical binding core of length different from nine. This previously undescribed mode of peptide binding to MHCII molecules gives a more complete picture of peptide presentation by MHCII and allows us to model more accurately this event.

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High‐resolution analysis of the murine MHC class II immunopeptidome

Cited by 48 publications

References 39 publications

The melting pot of the MHC II peptidome

The melting pot of the MHC II peptidome

Tools to define the melanoma‐associated immunopeptidome

Machine learning reveals a non‐canonical mode of peptide binding to MHC class II molecules

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