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HLA-DM-mediated HLA-DR3 Immunopeptidome

ABSTRACT: T2 cells stably expressing HLA-DR3 and variable amounts of HLA-DM (none, low, and high, per GFP co-expression) were lysed and HLA-DR3-peptide complexes were isolated via immunoprecipitation. Antigenic peptides were then eluted and quantified by LC-MS/MS to assess presented antigenic epitopes.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Eliot Morrison

LAB HEAD: Christian Freund

PROVIDER: PXD008775 | Pride | 2018-04-16

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	17_04_25_human_fbs_HEL_MBP_2.fasta	Fasta
	2017-07-26_BK28_T2-DR3_DM11_A01.raw	Raw
	2017-07-26_BK28_T2-DR3_DM11_A02.raw	Raw
	2017-07-26_BK28_T2-DR3_DM11_A03.raw	Raw
	2017-07-26_BK28_T2-DR3_DM11_A04.raw	Raw

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Publications

Quantification of HLA-DM-Dependent Major Histocompatibility Complex of Class II Immunopeptidomes by the Peptide Landscape Antigenic Epitope Alignment Utility.

Álvaro-Benito Miguel M Morrison Eliot E Abualrous Esam T ET Kuropka Benno B Freund Christian C

Frontiers in immunology 20180503

The major histocompatibility complex of class II (MHCII) immunopeptidome represents the repertoire of antigenic peptides with the potential to activate CD4<sup>+</sup> T cells. An understanding of how the relative abundance of specific antigenic epitopes affects the outcome of T cell responses is an important aspect of adaptive immunity and offers a venue to more rationally tailor T cell activation in the context of disease. Recent advances in mass spectrometric instrumentation, computational po ...[more]

PMID: 29774024

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HLA-DM allotypes - Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation

Project description:Major Histocompatibility Complex of Class II (MHCII) antigen presentation is a key event of adaptive immunity. HLA-DM favors the presentation of kinetically stable peptide-MHCII complexes but does not bind peptides itself and exhibits only a low degree of polymorphism. To date, no evidence for altered function of DM due to natural variations has been reported. We define the presence of DM haplotypes in human populations covered by the 1000 Genomes Project and probe their activity in antigen presentation assays. Our results indicate a clear linkage between DMA*0103 and DMB*0107 never reported before. Thehe corresponding heterodimer features a distinct activity profile when compared to the most frequent allotype (DMA*0101-DMB*0101). In vitro experiments demonstrate a broader pH activity profile for the new allotype, explaining its characteristic cellular function. Together, our results suggest that natural variations of DM have important consequences for an individual’s adaptive immune response.

2018-10-31 | PXD009791 | Pride

T-cell alloreactivity to HLA-DP is regulated by peptide repertoire divergence and HLA-DM mediated editing

Project description:Analysis of the peptide repertoires eluted from different HLA-DP molecules expressed in HeLa cells co-expressing Invariant chain either with or without HLA-DM as components of the HLA class II processing machinery. Divergence of the immunopeptidomes and the impact of HLA-DM were investigated in relation to the capacity of HLA-DP molecules to elicit alloreactive T-cell responses.

2022-11-21 | PXD017154 | Pride

Tuning DO:DM ratios modulates HLA class II immunopeptidomes

Project description:Major Histocompatibility Complex Class II antigen presentation underlies a wide range of immune responses in health and disease. Although peptide ligand binding affinity has been the major focus for explaining and predicting class II antigens, we know that the levels and activities of accessory molecules, HLA-DM (DM) and HLA-DO (DO) can have strong effects on peptide repertoires. However, the extent to which these antagonistic proteins’ levels relative to one another shape the identities and properties of peptides selected for presentation remains unclear. Hence, after creating cell line panel with varying DO:DM ratios, of we set out to measure the effects these ratios can have on peptide presentation. Using a combined immunopeptidomic and proteomic discovery strategy, we profiled ligandome differences across this panel. By surveying over 10,000 unique HLA-DR4-presented peptides, we found marked increases in repertoire diversity and altered physical properties of presented peptides that corresponded with increasing DO:DM ratios.

2023-10-24 | PXD024392 | Pride

Unsupervised mining of HLA-I peptidomes reveals unsuspected false positives and new binding motifs

Project description:Modern antigen vaccine designs and studies of human leukocyte antigen (HLA)-mediated immune responses rely heavily on the knowledge of HLA allele-specific binding motifs and computational prediction of antigen-HLA binding affinity. Breakthroughs in HLA peptidomics have considerably expanded the databases of natural HLA antigens and enabled detailed characterizations of antigen-HLA binding specificity. However, cautions must be made when analyzing HLA peptidomics data because identified peptides may be contaminants or may weakly bind to the HLA molecules. Here, a hybrid de novo peptide sequencing approach was applied to large-scale mono-allelic HLA peptidomics datasets to uncover new antigens and refine current knowledge of HLA binding motifs. Up to 12-40% contaminations in the form of tryptic peptides were identified in the peptidomics data of HLA alleles whose binding motifs do not involve an arginine or a lysine at the C-terminus. Thousands of these peptides were reported in a community database as positive antigens and might be erroneously used to train prediction models. Furthermore, unsupervised clustering of identified antigens not only revealed additional binding motifs for several HLA class I alleles but also effectively isolated outliers which were confirmed to be false positives in a binding experiment. Overall, our findings expanded the knowledge of HLA binding specificity and indicated that a more careful HLA peptidomics data interpretation protocol is needed to ensure the high quality of community antigen databases.

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Tumour-associated antigenic peptides are present in the HLA class I ligandome of cancer cell line derived extracellular vesicles.

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2022-04-01 | PXD025345 | Pride

pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic activity.

Project description:The peptide-exchange catalyst, HLA-DM, and its inhibitor, HLA-DO control endosomal generation of peptide/class II major histocompatibility protein (MHC-II) complexes; these complexes traffic to the cell surface for inspection by CD4+ T cells. Some evidence suggests that pH influences DO regulation of DM function, but pH also affects the stability of polymorphic MHC-II proteins, spontaneous peptide loading, DM/MHC-II interactions and DM catalytic activity, imposing challenges on approaches to determine pH effects on DM-DO function and their mechanistic basis. Using optimized biochemical methods, we dissected pH-dependence of spontaneous and DM-DO-mediated class II peptide exchange and identified an MHC-II allele-independent relationship between pH, DO/DM ratio and efficient peptide exchange. We demonstrate that active, free DM is generated from DM-DO complexes at late endosomal/lysosomal pH due to irreversible, acid-promoted DO destruction rather than DO/DM molecular dissociation. Any soluble DM that remains in complex with DO stays inert. pH-exposure of DM-DO in cell lysates corroborates such a pH-regulated mechanism, suggesting acid-activated generation of functional DM in DO-expressing cells.

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