DYNAMICS AND TUNING OF THE MHC II PRESENTED PEPTIDOME

MHC II 呈递肽段的动力学和调节

• 批准号: 10016167
• 负责人: LAURA SANTAMBROGIO
• 金额: $ 82.04万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016167
• 关键词: Address; Adolescent; Affect; Affinity; Anatomy; Antigen Presentation; Antigen-Presenting Cells; Attention; Autoantigens; Autoimmune Diseases; Autoimmunity; Binding; Binding Proteins; Biological Assay; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cell Maturation; Cervical; Chromogranins; Chronic Childhood Arthritis; Clonal Expansion; Collagen; Collagen Type II; Crohn' s disease; Dendritic Cells; Development; Diabetes Mellitus; Disease; Epitopes; Equilibrium; Generations; Goals; Harvest; Histones; Immune; Immune system; Immunity; Immunologics; In Vitro; Inbred NOD Mice; Individual; Infection; Inflammation; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Isotope Labeling; Label; Location; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Measurement; Mediating; Methodology; Modeling; Monitor; Multiple Sclerosis; Mus; Organ; Pancreas; Pathologic; Pathway interactions; Peptides; Phase; Physiological; Population; Post-Translational Protein Processing; Prealbumin; Prediabetes syndrome; Process; Proteins; Proteomics; Reproducibility; Rest; Rheumatoid Arthritis; Salmonella typhimurium; Sampling; Serum Proteins; Source; Stimulus; Surveys; System; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; Testing; Time; Tissues; Tuberculosis; adaptive immune response; antigen processing; autoreactive T cell; base; central tolerance; draining lymph node; experimental study; extracellular; in vivo; in vivo monitoring; instrumentation; insulitis; islet; lymph nodes; mesenteric lymph node; pathogen; peripheral tolerance; prevent; proteomic signature

This application addresses fundamental open questions on MHC-II peptidome selection and composition, namely, the plasticity of the MHC-II peptidome displayed by conventional dendritic cells (cDC) at different organ locations and under physiological and pathological conditions. Overall our analysis will generate a quantitative mapping of (i) how the MHC-II peptidome reflects the “organ- specific proteomic signature” from where the cDC originates and (ii) the relationship between presented MHC II peptidome in resting and inflammatory conditions, for both self and non-self-epitopes. Aim 1 is to understand how qualitative and quantitative changes in MHC II epitope copy number presented in local lymph node contribute to the balance between tolerance and autoimmunity. The MHC II peptidome will be compared among cDC harvested from lymph nodes draining different organs and quantitative mass spectrometry will be utilized to monitor changes in the immune-peptidome and peptide abundance across tissue cDC. In particular we will quantify the peptide copy numbers on local cDC for tissue specific self antigens, known to be targets in autoimmune diseases and whose auto-reactive T cells are found in the periphery, including MBP, PLP, MOG, (multiple sclerosis) D1-antitrypsin (Crohn's disease), Insulin, GAD65, Chromogranin, (diabetes type I), histones, (systemic lupus erythematosus) and collagen II (rheumatoid arthritis) and Transthyretin (RA and juvenile idiopathic arthritis). Additionally we will use the well- characterized NOD mice Type 1 Diabetes model to answer the question of whether when mice cross the threshold between physiological conditions and pre-diabetic insulitis quantitative and qualitative changes in the I-Ag7-peptidome associated with disease development (insulin, chromogranin, GAD65, S100), are observed. Aim 2 is to understand the consequences of infection and inflammation on the MHC II-self peptidome . Using quantitative isotope labeling and label-free proteomic approaches we will monitor the in vivo presented self- and noself-peptidomes presented cDC in resting mice and after infection with Mycobaterium tuberculosis or Salmonella typhimurium, to determine how the cDC maturation process changes the presented MHC-II self peptidome. We will determine any changes in MHC II affinity and HLA-DM sensitivity in the MHC II self- peptidome induced by infection, and differences in the MHC II antigen processing pathways in immature and pathogen-matured cDC. Finally, we evaluate how changes in post-translational modification processing induced during DC maturation impact the presented peptidome. Overall these studies will determine how MHC II epitope copy number presented in local lymph node can contributes to the balance between tolerance and autoimmunity and what are the consequences of infection and inflammation on the displayed MHC II self peptidome.

这个应用程序解决了MHC-II肽丘选择和组成的基本开放问题。