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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要卵泡辅助器（TFH）细胞和相关亚群的扩展与人类的严重程度相关狼疮性疾病，并由所有容易发生狼疮的小鼠模型共享。但是，扩展的机制狼疮中的TFH细胞在很大程度上未知。因此，该提议的目的是为机制开发新的启示使用创新的细胞和分子方法基于狼疮的TFH细胞扩张的原因从b6.sle1.sle2.sle3三重先天（TC）鼠模型中获得的数据。因此，我们已经确定了调节狼疮TFH细胞膨胀的遗传以及微生物和代谢决定因素。将狼疮小鼠的干扰肠道菌群转移到对TFH细胞至关重要的小鼠宿主中扩张。此外，色氨酸（TRP）代谢改变也增强了TFH细胞的扩张，这是通过操纵小鼠的饮食TRP水平减少。最后，用2-Deoxi-D-葡萄糖（2DG）抑制糖酵解，或用6-二二氮-5氧化氧基-L-甲酸氨酸氨基氨酸（DON）功能降低狼疮TFH细胞分化的谷氨酰胺溶解。我们的假设是，与狼疮有关的TFH细胞的膨胀会整合来自易感基因的线索，微生物组和环境代谢产物失调。为了支持这一假设，我们的数据证明了 TC TFH细胞具有一种新型的代谢基因特征，有可能驱动自动反应性TFH细胞扩展由独特的代谢通量执导。因此，我们提出结合TFH细胞转录组和代谢组响应上述提示的变化，以阐明所涉及的分子单独或组合的机制影响了狼疮中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细胞在两个B细胞子集上的影响， CD11C+ TBET+ B细胞（ABC）和IgA+ B细胞。为了进行，提出了以下具体目标。 1 探索狼疮易感性基因调节TFH细胞转录组和两个无关的TC和（NZW x BXSB.YAA）F1狼疮模型中的代谢组。 2。确定 TC小鼠中TFH转录组和代谢组的环境因素。 3。阐明分子与狼疮患者中TFH细胞扩张有关的机制。从这些机制中获得的结果实验将是对环境和遗传指导的TFH细胞扩张的深入研究决定因素，可以重新编程以作为可持续的治疗策略，以改善狼疮患者的健康。