Determinants of follicular helper T cell expansion in lupus

狼疮滤泡辅助 T 细胞扩张的决定因素

• 批准号: 10065726
• 负责人: Laurence Morel
• 金额: $ 63.21万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10065726
• 关键词: Affect; Affinity; Autoantibodies; Automobile Driving; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Congenic Mice; Cues; Data; Diet; Disease; Disease Outcome; Drug or chemical Tissue Distribution; Environmental Impact; Environmental Risk Factor; Exhibits; Frequencies; Genes; Genetic; Genetic Determinism; Genome; Glucose; Glutamine; Glycolysis; Health; Helper-Inducer T-Lymphocyte; Human; ITGAX gene; Immunoglobulin A; Immunoglobulin Class Switching; Investigation; Knowledge; Light; Lupus; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Norleucine; Outcome; Pathogenicity; Pathway interactions; Patients; Peripheral; Production; Reagent; SLEB1 gene; SLEB3 gene; Severities; Severity of illness; Spleen; Susceptibility Gene; Systemic Lupus Erythematosus; T-Lymphocyte Subsets; Testing; Therapeutic; Tryptophan; Tryptophan Metabolism Pathway; Validation; Variant; autoreactivity; base; cohort; congenic; dysbiosis; experimental study; fecal microbiota; follow-up; genetic signature; gut microbiota; improved; in vitro Assay; in vivo; innovation; lupus prone mice; metabolome; metabolomics; microbial; microbiome; mouse model; novel; programmed cell death protein 1; response; solute; synergism; transcriptome; transcriptome sequencing; transcriptomics

Project Summary/Abstract The expansion of follicular helper (Tfh) cells and related subpopulations is correlated with the severity of human lupus disease and is shared by all lupus-prone mouse models. However, the mechanisms for the expansion of Tfh cells in lupus are largely unknown. Thus, the objective of this proposal is to shed new light on the mechanisms that are responsible for Tfh cell expansion in lupus using innovative cellular and molecular approaches based on the obtained data from the B6.Sle1.Sle2.Sle3 triple congenic (TC) murine model of lupus. Accordingly, we have identified genetic, as well as microbial and metabolic determinants that modulate lupus Tfh cell expansion. Transferring the perturbed gut microbiota of lupus mice into mouse host crucially contributed to Tfh cell expansion. Additionally, an altered tryptophan (Trp) metabolism also enhanced Tfh cell expansion, which was reduced by manipulating dietary Trp levels in mice. Finally, inhibiting glycolysis with 2-deoxi-D-glucose (2DG), or glutaminolysis with 6-Diazo-5-oxo-L-norleucine (DON) functionally diminished lupus Tfh cell differentiation. Our hypothesis is that the expansion of Tfh cells implicated in lupus integrates cues from susceptibility genes, dysregulated microbiome and environmental metabolites. In support of this hypothesis, our data demonstrate that TC Tfh cells possess a novel metabolic gene signature, potentially driving the autoreactive Tfh cell expansion directed by a unique metabolic flux. Thus, we propose combining the analyses of Tfh cell transcriptome and metabolome in response to variations of the aforementioned cues as a means to elucidate the involved molecular mechanisms, singly or in combination, impacting the fate of Tfh cells in lupus. We also propose to investigate the effects of genetic and environmental determinants functionally affecting Tfh cells on two B cell subsets, CD11c+Tbet+ B cells (ABCs) and IgA+ B cells. To proceed, the following Specific Aims are proposed. 1. To explore the mechanisms by which lupus susceptibility genes modulate the Tfh cell transcriptome and metabolome in the two unrelated TC and (NZW x BXSB.Yaa)F1 lupus models. 2. To identify the impact of environmental factors on the Tfh transcriptome and metabolome in TC mice. And 3. To elucidate the molecular mechanisms implicated in the expansion of Tfh cells in lupus patients. Obtained results from these mechanistic experiments will be the first in-depth investigation of Tfh cell expansion directed by environmental and genetic determinants, which may be reprogrammed for a sustainable therapeutic strategy to perhaps improve lupus patients' health.

项目概要/摘要 滤泡辅助细胞 (Tfh) 和相关亚群的扩张与人类疾病的严重程度相关 狼疮疾病，是所有狼疮易感小鼠模型所共有的。然而，扩大规模的机制 狼疮中的 Tfh 细胞很大程度上是未知的。因此，该提案的目的是为机制提供新的启示 使用基于创新的细胞和分子方法负责狼疮中 Tfh 细胞的扩增 根据从 B6.Sle1.Sle2.Sle3 三重同源 (TC) 狼疮小鼠模型获得的数据。据此，我们 已经确定了调节狼疮 Tfh 细胞扩张的遗传、微生物和代谢决定因素。 将狼疮小鼠受干扰的肠道微生物群转移到小鼠宿主中对 Tfh 细胞的形成至关重要 扩张。此外，色氨酸 (Trp) 代谢的改变也增强了 Tfh 细胞的扩增，这 通过控制小鼠饮食中的色氨酸水平来减少。最后，用 2-脱氧-D-葡萄糖 (2DG) 抑制糖酵解， 或用 6-Diazo-5-oxo-L-norleucine (DON) 进行谷氨酰胺分解可功能性降低狼疮 Tfh 细胞分化。 我们的假设是，与狼疮有关的 Tfh 细胞的扩增整合了来自易感基因的线索， 失调的微生物组和环境代谢物。为了支持这一假设，我们的数据表明 TC Tfh 细胞拥有新的代谢基因特征，可能驱动自身反应性 Tfh 细胞扩增 由独特的代谢流引导。因此，我们建议结合 Tfh 细胞转录组的分析和 代谢组响应上述线索的变化作为阐明所涉及分子的手段 单独或组合的机制影响狼疮中 Tfh 细胞的命运。我们还建议调查 遗传和环境决定因素在功能上影响 Tfh 细胞对两个 B 细胞亚群的影响， CD11c+Tbet+ B 细胞 (ABC) 和 IgA+ B 细胞。为此，提出以下具体目标。 1. 至 探讨狼疮易感基因调节 Tfh 细胞转录组的机制 两个不相关的 TC 和 (NZW x BXSB.Yaa)F1 狼疮模型中的代谢组。 2. 确定影响 环境因素对 TC 小鼠 Tfh 转录组和代谢组的影响。 3. 阐明分子 狼疮患者 Tfh 细胞扩增的机制。从这些机制中得到的结果 实验将是对环境和遗传指导下的 Tfh 细胞扩增的首次深入研究 决定因素，可以重新编程以形成可持续的治疗策略，以改善狼疮 患者的健康。