Manipulating & imaging nutrient micro-milieux as B cells effect humoral immunity

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基本信息

批准号：
10529278
负责人：
Mark R Boothby
金额：
$ 52.54万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10529278
关键词：
Affect Affinity Amino Acids Animal Experiments Antibodies Antibody Response B Cell Proliferation B cell differentiation B-Lymphocytes Biological Blood Circulation Cell Differentiation process Cell physiology Cells Chromatin Complex Critical Illness Data Defect Development Diet Effectiveness Elements Endocrine Environment Epigenetic Process Equilibrium Experimental Models FRAP1 gene Gene Expression Regulation Generations Glucagon Receptor Glucose Glutamates Glutaminase Glutamine Haptens Health Histones Human Humoral Immunities Hypoxia IgE IgG1 Image Immune Immune response Immunity Immunization Immunoglobulin Class Switching Impairment In Vitro Infection Link Lymphocyte Lymphocyte Function Lymphoid Lymphoid Follicle Lysine Malnutrition Malpighian corpuscles Mass Spectrum Analysis Mature B-Lymphocyte Measures Mediator Memory Memory B-Lymphocyte Metabolic Metabolism Methylation Microanatomy Microbe Modeling Molecular Nature Nutrient Nutritional status Organ Outcome Patients Pattern Permeability Physiological Plasma Cells Precursor B-Lymphoblast Process Proliferating Protein Deficiency Proteins Regulation Reporting Rodent Scientist Set protein Signal Pathway Signal Transduction Spleen Structure of germinal center of lymph node T-Lymphocyte Testing Vaccination Vaccines Venous Visualization Work adaptive immunity alpha ketoglutarate cell type chromatin modification density deprivation electric impedance experimental study genomic locus histone methylation in vivo interstitial loss of function lymph nodes lymphocyte proliferation mass spectrometric imaging microbiome novel novel strategies nutrition oxidation plasma cell differentiation restraint sensor vaccine efficacy virtual

项目摘要

Project Summary Generating antibodies, refining their qualities, and creating durable humoral memory are crucial parts of adaptive immunity. The capacity of vaccines to protect against microbes draws on each facet of these processes, but even for some approved and useful vaccines the efficacy is needs to be better. Accordingly, it is vital to decipher key cellular and molecular processes that affect antibody (Ab) qualities. Major efforts are directed toward the identification of ways in which intracellular sensors, mediators of intermediary metabolism, and metabolites proper alter immune cell differentiation or function. It has long been known that malnutrition undermines immune defenses against infection, and a body of work has suggested that protein deficiency may decrease effective Ab responses. Nutrient supply is intrinsically linked to intracellular sensors such as mTORC1 and programming of cellular metabolism in immune cells. For instance, experimental models of isolated protein deficiency have documented decreases in venous concentrations of amino acids (a.a.) and lower mTORC1 activity in freshly isolated organs from the malnourished rodents. Our work on mTORC1 in B cells found antibody responses to be altered by B cell-restricted haplo-insufficiency of Raptor, with partially reduced activity similar in magnitude to that reported in the setting of protein deprivation. Moreover, we – and others in parallel – uncovered evidence of variegated hypoxia in the white pulp and lymphoid follicles after immunization and formation of germinal centers. Preliminary in vitro and in vivo experiments provide evidence that (a) glutamine, at the physiological concentration of non-inflamed interstitia, is limiting for fully efficient switching to IgG1 and for plasma cell differentiation, and (b) glutaminolysis (the conversion of glutamine to glutamate, and then α-ketoglutarate) can be limiting for these processes. These findings are the premise for the overarching model of this application: that nutrients may be present in follicles at concentrations where either increases or further decreases alter the nature of the antibody response as it draws on lymphocyte proliferation and function. Accordingly, in Aim 1 we will test the impact on Ab responses of reducing a.a. supply to or utilization by mature B cells. Aim 2 will identify consequences for metabolic and epigenetic programming of the B cells in which glutamine supply or glutaminolysis are restricted, alone or with reduced glucose oxidation capacity. An implication of the model is that increased circulating a.a. – or even just glutamine – could enhance outcomes of immunization. In Aim 3, we will use a newly identified endocrine approach to test if hyperaminoacidemia increases interstitial glutamine and yields greater Ab responses or humoral memory. As a novel facet of the experiments, we will leverage a state-of the-art development in imaging mass spectrometry (IMS) to assess glutamine and selected metabolites in selected lymphoid micro-environments of experimental animals. The expected outcome & impact of the proposed studies are that we will (i) provide a ground-breaking technical advance in application of IMS to biological problems, (ii) elucidate a long-standing issue at the nexus of nutrition and immunity, and (iii) identify a novel means of boosting antibody responses.