Dataset Information

Tuning DO:DM ratios modulates HLA class II immunopeptidomes

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Leukocyte

DISEASE(S): Lymphoblastic Lymphoma

SUBMITTER: Niclas Olsson

LAB HEAD: Joshua E. Elias

PROVIDER: PXD024392 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

Tuning DO:DM Ratios Modulates MHC Class II Immunopeptidomes.

Olsson Niclas N Jiang Wei W Adler Lital N LN Mellins Elizabeth D ED Elias Joshua E JE

Molecular & cellular proteomics : MCP 20220125 3

Major histocompatibility complex class II (MHC-II) antigen presentation underlies a wide range of immune responses in health and disease. However, how MHC-II antigen presentation is regulated by the peptide-loading catalyst HLA-DM (DM), its associated modulator, HLA-DO (DO), is incompletely understood. This is due largely to technical limitations: model antigen-presenting cell (APC) systems that express these MHC-II peptidome regulators at physiologically variable levels have not been described. ...[more]

PMID: 35085787

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Project description:All nucleated mammalian cells express major histocompatibility complex (MHC) proteins that present peptides on cell surfaces for immune surveillance. These MHC-presented peptides (pMHC) can convey non-self antigens derived from pathogens or mutations to amount T-cell responses. Alterations in tumor-specific antigens – particularly mutation-bearing peptides (neoantigens) presented by MHC — can serve as potent substrates for anti-tumor immune responses. Here we employed an integrated genomic and proteomic antigen discovery strategy aimed at measuring interferon gamma (IFN-γ) induced alterations to antigen presentation, using a lymphoma cell line. IFN-γ treatment resulted in a set of differentially expressed proteins (2 % of all quantified proteins) including components of antigen presentation machinery or interferon signaling pathways. In addition, several proteasome subunits were found to be modulated, consistent with previous reports of immunoproteasome induction by IFN-γ exposure. This finding suggests that a modest proteomic response to IFN-γ could create larger alteration to cells antigen repertoires. Accordingly, by surveying immunopeptides, distinct peptide repertoires were exclusively observed in the IFN-γ induced samples. Furthermore, an additional set of presented peptides distinguished control and the IFN-γ samples by their altered relative abundances including neoantigens. Accordingly, we developed a classification system to distinguish peptides which are differentially presented due to altered expression from novel peptides resulting from changes in antigen processing. Taken together, these data demonstrate that IFN-γ can re-shape antigen repertoires by identity and by abundance. Extending this approach to models with greater clinical relevance should help develop strategies by which immunopeptide repertoires are intentionally reshaped to improve endogenous or vaccine-induced anti-tumor immune responses and potentially anti-viral immune responses.

Project description:Diabetes mellitus (DM) is a disorder that disrupts the body from shifting glucose into the cells resulting in hyperglycaemia (1). Insulin dependence or DM that resembles type I diabetes in humans is commonly observed in dogs (2). Canine DM diagnosis is based on fasting hyperglycaemia and glucosuria with clinical presentation of polyuria, polydipsia, polyphagia and weight loss (2). Its treatment goal is blood glucose control, which can be accomplished through insulin therapy, dietary modification and control of concurrent disorders (3). The major complications of DM include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and atherosclerosis induced by chronic hyperglycaemia via several pathways (4). The proposed unifying mechanism that mediates the tissue-damaging effects of hyperglycaemia is superoxide overproduction (5). Effective monitoring is required for DM treatment to reduce the risk of progression and complication. Hence, the identification of novel biomarkers is being researched (6, 7). Proteomics has been recognised as an important tool for establishing a diagnosis of disease aetiology and monitoring therapy outcomes (8, 9). Proteomic patterns were applied to detect diabetes and complications, as well as to evaluate treatment effectiveness in humans (10-12). There is limited information on proteomic data in DM dogs (13-15). In a proteomic analysis of serum samples from DM dogs, most upregulated proteins are involved in oxidative state, defence and inflammation (13). Medicinal plants are utilised in DM dogs as an adjunct medicine in combination with standard treatment to prevent the development of long-term diabetes complications and improve overall well-being. Curcumin, the most phytochemically active curcuminoid extracted from Curcuma longa, has gained attention in human and laboratory animals. Curcumin is known to have antioxidant, anti-inflammatory and anticancer properties (16-18). In humans and experimental animals with DM, curcumin has an antioxidant potential of enhanced reduced glutathione (GSH) and reduced malondialdehyde (MDA) levels (19, 20). The anti-inflammatory effects of curcumin in DM were reported via decreased interleukin-1β (IL‐1β), interleukin-6 (IL‐6), interleukin-8 (IL‐8) and tumour necrosis factor-α levels and also diminished monocyte chemoattractant protein-1 and C-reactive protein levels (19-21). There has been no published evidence of the impact, safety and proteomic profiles of curcuminoids, particularly curcumin, in client-own DM dogs. Accordingly, the aims of the present study were (1) to evaluate the effects of curcuminoid supplementation on canine DM-associated oxidative stress and inflammation, (2) to determine the safety of curcuminoid supplementation in canine diabetes and (3) to determine whether curcuminoid has an impact on proteins implicated in DM-associated complications by a proteomic analysis.

Dataset Information

Tuning DO:DM ratios modulates HLA class II immunopeptidomes

Publications

Tuning DO:DM Ratios Modulates MHC Class II Immunopeptidomes.

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