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

适合记住吗？

• 批准号: 8888712
• 负责人: Mark R Boothby
• 金额: $ 19.63万
• 依托单位: VANDERBILT UNIVERSITY
• 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/8888712
• 关键词: 5' -AMP-activated protein kinase; Address; Adoptive Transfer; Affinity; Alleles; Anabolism; Antibodies; Antibody Formation; Antibody Response; Antidiabetic Drugs; Antigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biochemical; Biological Models; Biology; CD8B1 gene; Cell Lineage; Cell Survival; Cell physiology; Cells; Characteristics; Clinical Data; Complement; Complex; Data; Disease; Epitopes; Equilibrium; Fostering; Generations; Glucose; Glycolysis; Health; Humoral Immunities; Hypoxia; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin M; In Vitro; Interleukin-4; Lead; Learning; Leukocytes; Life; Lipids; Lymphoid; Maintenance; Measures; Mediating; Memory; Memory B-Lymphocyte; Metabolic; Metabolic Pathway; Metabolism; 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; Staging; 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; mTOR protein; 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（由申请人提供）：体液记忆是适应性免疫和一些自身免疫性疾病的关键特征，对于疫苗预防微生物的能力至关重要。这一过程的决定因素包括生发中心 (GC) 和滤泡外反应促进各类记忆 B (Bmem) 细胞分化和维持的程度，而回忆反应正是从这些细胞中产生的。人们对 B 细胞激活后的潜在命运了解很多，包括 BCR 对 Ag 亲和力的重要贡献，但对 B 细胞内的信号传导如何影响记忆或回忆却知之甚少。通过体外操作和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）与免疫系统细胞信号传导及其命运或功能特征之间的调节相互作用的迹象。 B 细胞独特的生物学特性表明它们使用新的机制，但人们对 B 淋巴谱系的代谢调节知之甚少，尤其是对 Bmem 细胞类别的持续存在或足够浓度的 Ab 的了解甚少。 AMP 激活激酶 (AMPK) 是二甲双胍等抗糖尿病药物的靶标，对于调节生物合成中能量产生与利用之间的平衡至关重要。我们发现 B 细胞中 AMPK 的主要亚型 AMPKa1 促进了 B 细胞内在作用中回忆 Ab 反应的能力。我们还发现了与 AMPK 平行的途径的证据，在该途径上，ADP-核糖基转移酶 PARP14 促进糖酵解、葡萄糖氧化和 B 细胞存活的增加。此外，几种抗体同种型的抗体反应依赖于 PARP14。这些和进一步的发现使我们推测 AMPKa 促进 Ag 特异性 IgG+ 记忆 B 细胞的生成或维持，并且这种功能至少部分是通过促进代谢适应性 [脂肪酸氧化 (FAO)、糖酵解和葡萄糖氧化] 来发挥的。该研究还将解决 CTL 记忆中心范式关键研究中尚未解决的悖论，其中 (FAO) 与记忆命运相关，而糖酵解与效应器样表型相关。难题在于平衡作用归因于 AMPK 活性，但这种激酶同时促进FAO和糖酵解。我们将检验以下假设：这些形式的能量产生的差异调节是基于缺氧诱导因子 (HIF - 1, 2) 的活性，这些转录因子可能会在糖酵解激活的同时直接抑制FAO。为了测试 AMPK 活性对体液回忆的影响，并阐明平衡代谢途径的机制，我们有三个具体目标。第一个目标（目标 1）是为记忆中的关键代谢调节因子 AMPK 建立特定的 B 谱系内在功能，并确定需要它的阶段。在目标 2 中，我们将测试一个模型，其中 HIF 与 AMPK 整合以设置 B 细胞代谢平衡并回忆 Ab 反应。最后，我们将评估 mTOR 是否是 B 细胞和体液记忆中 AMPK 的效应子（目标 3）。拟议研究的预期结果是，我们将发现 AMPK 和 HIF-1 在确定 B 细胞代谢特征和体液免疫功能结果方面的新作用。