Fit to remember? B cell metabolic 'fitness', AMPK & recall antibody responses

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• 批准号: 9204785
• 负责人: Mark R Boothby
• 金额: $ 39.5万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204785
• 关键词: 5' -AMP-activated protein kinase; Address; Adoptive Transfer; Affinity; Alleles; Anabolism; Anaerobic Bacteria; Anatomy; Antibodies; Antibody Formation; Antibody Response; Antidiabetic Drugs; Antigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biochemical; Biological Models; Biology; CD8B1 gene; Cell Differentiation process; Cell Lineage; Cell Survival; Cells; Cellular Metabolic Process; Characteristics; Clinical Data; Complement; Complex; Data; Disease; Epitopes; Equilibrium; FRAP1 gene; Fostering; Generations; Glucose; Glycolysis; Health; Humoral Immunities; Hypoxia; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin M; In Vitro; Interleukin-4; Lead; Leukocytes; Lipids; Lymphoid; Maintenance; Measures; Mediating; Memory; Memory B-Lymphocyte; Metabolic; Metabolic Pathway; Metformin; Microbe; Modeling; Mus; Nature; Nutrient; Outcome; Pathway interactions; Performance; Phenotype; Phosphotransferases; Physiology; Plasma Cells; Population; Process; Protein Isoforms; Proteins; Reaction; Regulation; Research; Role; STAT6 gene; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Systems Development; T-Lymphocyte; Testing; Transferase; Transgenes; Vaccines; Work; adaptive immunity; anaerobic glycolysis; base; clinical practice; effective therapy; fatty acid oxidation; fitness; functional outcomes; gain of function; improved; long term memory; loss of function; metabolic profile; mouse model; novel; oxidation; public health relevance; response; sensor; transcription factor; vaccine efficacy

 DESCRIPTION (provided by applicant): Humoral memory, a key feature of both adaptive immunity and some autoimmune diseases, is central to the capacity of vaccines to protect against microbes. Determinants of this process include the degrees to which germinal center (GC) and extrafollicular reactions foster the differentiation and maintenance of various classes of memory B (Bmem) cells from which recall responses are derived. Much has been learned about the potential fates of a B cell after its activation, including vital contributions of BCR affinity for Ag, but remarkably little is known about how signaling within the B cell impacts memory or recall. Accumulating evidence with in vitro manipulations as well as mouse model systems provides indications of a regulatory interplay of local physiology (e.g., nutrient supply) with signaling in cells of the immune system and their fate or functional characteristics. The unique biology of B cells suggests that they use novel mechanisms, but very little is known about metabolic regulation for the B lymphoid lineage and especially not for the persistence of classes of Bmem cells or adequate concentrations of Ab. AMP-activated kinase (AMPK), a target of anti-diabetic agents such as metformin, is central to regulation of the balance between energy generation versus utilization in bio-synthesis. We have found that the predominant isoform of AMPK in B cells, AMPKa1, promoted the capacity for a recall Ab response in a B cell- intrinsic role. We also developed evidence of a pathway parallel to AMPK, on which an ADP-ribosyl transferase, PARP14, promotes increases in glycolysis, glucose oxidation, and B cell survival. Moreover recall Ab responses of several Ab isotypes depended on PARP14. These and further findings lead us to hypothesize that AMPKa promotes the generation or maintenance of Ag-specific IgG+ memory B cells, and that this function is exerted at least in part through promotion of metabolic fitness [fatty acid oxidation (FAO), glycolysis, and glucose oxidation]. The research also will address an unresolved paradox from key studies of the central paradigm of CTL memory, in which (FAO) is associated with memory fate while glycolysis ties to effector-like phenotype. The conundrum is that the balancing act was attributed to AMPK activity, but this kinase promotes both FAO and glycolysis. We will test the hypothesis that differential regulation of these forms of energy generation is based on activity of hypoxia- induced factor(s) (HIFs - 1, 2), transcription factors that may directly repress FAO alongside its activation of glycolysis. To test the impact of AMPK activity on humoral recall, and elucidate a mechanism by which metabolic pathways can be balanced, we have three specific Aims. The first (Aim 1) is to establish a specific B lineage- intrinsic function for the key metabolic regulaor, AMPK, in memory and identify stages at which it is required. In Aim 2, we will test a model in which HIFs are integrated with AMPK in setting B cell metabolic balance and recall Ab responses. Finally, we will evaluate if mTOR is an effector of AMPK in B cells and humoral memory (Aim 3). The expected outcome of the proposed studies is that we will uncover novel roles for AMPK and HIF- 1 in determining the metabolic profile in B cells and functional outcomes in humoral immunity.

 描述（适用提供）：体液记忆，自适应免疫学和某些自身免疫性疾病的关键特征，是疫苗预防微生物的能力的核心。该过程的决定因素包括生发中心（GC）和毛囊外反应的程度促进了各种记忆B（BMEM）细胞的分化和维护，从而从中得出了回忆反应。关于B细胞激活后的潜在命运的知识已经很多，包括BCR对AG的重要贡献，但对于B细胞中的信号如何影响记忆或回忆的信号传导几乎没有什么了解。通过体外操纵以及小鼠模型系统积累的证据提供了局部生理学（例如，营养供应）与免疫系统细胞中信号传导的调节性相互作用及其命运或功能特征。 B细胞的独特生物学表明它们使用了新型机制，但是对于B淋巴样谱系的代谢调节，尤其是对于BMEM细胞类别的持续或适当浓度的AB的代谢调节知之甚少。 AMP激活激酶（AMPK）是抗糖尿病药物（例如二甲双胍）的靶标，是调节生物合成中能量产生与利用之间平衡的核心。我们已经发现，AMPKA1在B细胞中AMPK的主要同工型促进了B细胞中性作用中召回AB反应的能力。我们还开发了与AMPK平行的途径的证据，ADP-核糖基转移PARP14可促进糖酵解，葡萄糖氧化和B细胞存活的增加。此外，回忆几种AB同种型的AB反应取决于PARP14。这些和进一步的发现使我们假设AMPKA促进了Ag特异性IgG+记忆B细胞的产生或维持，并且至少通过促进代谢适应性[脂肪酸氧化（FAO），糖酵解，糖酵解和糖糖氧化]至少在某种程度上执行此功能。这项研究还将解决CTL记忆中心范式的关键研究中未解决的悖论，其中（FAO）与记忆命运相关联，而糖酵解与效应类似于效应的表型。难题是平衡行为归因于AMPK活性，但这种激酶既促进了粮农组织和糖酵解。我们将检验以下假设：这些形式的能量产生形式的差异调节是基于缺氧诱导因子的活性（HIFS -1，2），即可能直接抑制FAO并在其激活糖基溶解并激活其激活的情况下转录因子。为了测试AMPK活性对体液召回的影响，并阐明了一种可以平衡代谢途径的机制，我们有三个特定的目标。第一个（AIM 1）是在内存中为关键代谢调节剂AMPK建立特定的B谱系 - 内在函数，并确定所需的阶段。在AIM 2中，我们将测试一个模型，其中HIF与AMPK集成在一起，以设定B细胞代谢平衡并回忆AB响应。最后，我们将评估MTOR是否是B细胞和体液记忆中AMPK的效应因子（AIM 3）。拟议的研究的预期结果是，我们将发现AMPK和HIF-1在确定B细胞中的代谢谱和体液免疫功能结果中的新作用。