Determinants of follicular helper T cell expansion in lupus

项目摘要/摘要 滤泡辅助细胞(TFH)及相关亚群的扩张与人类疾病的严重程度相关 狼疮性疾病，所有狼疮易感小鼠模型都有这种现象。然而，扩大的机制， 狼疮中的TFH细胞在很大程度上是未知的。因此，这项提案的目标是对这些机制作出新的解释。 使用创新的细胞和分子方法在狼疮中负责TFH细胞的扩张 根据B6.Sle1.Sle2.Sle3三基因同源(TC)狼疮小鼠模型所获得的数据。因此，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。 将狼疮小鼠扰动的肠道微生物区系转移到小鼠宿主体内对TFH细胞的形成至关重要 扩张。此外，色氨酸(Trp)代谢的改变也促进了TFH细胞的扩张，这是 通过控制小鼠饮食中的色氨酸水平来降低。2-脱氧-D-葡萄糖(2DG)抑制糖酵解， 6-重氮-5-氧代-L去亮氨酸(DON)对狼疮Tfh细胞分化的抑制作用。 我们的假设是，与狼疮有关的TFH细胞的扩张整合了易感基因的线索， 微生物群和环境代谢物的失调。为了支持这一假设，我们的数据表明 TC Tfh细胞具有新的代谢基因信号，潜在地驱动自身反应性Tfh细胞的扩张 由一种独特的新陈代谢流引导。因此，我们建议将TFH细胞转录组的分析与 代谢组对上述信号变化的反应作为阐明相关分子的一种手段 影响狼疮中TFH细胞命运的单独或联合机制。我们还提议调查 影响Tfh细胞功能的遗传和环境决定因素对两个B细胞亚群的影响， CD11c T细胞(ABCs)和IgA B细胞。为此，提出了以下具体目标。1.至 探讨狼疮易感基因调控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 环境因素对TC小鼠转铁蛋白转录组和代谢组的影响。3.阐明分子 狼疮患者TFH细胞增殖机制的研究。从这些机械论中获得的结果 实验将是第一次深入研究环境和遗传指导下的TFH细胞扩增 决定因素，可能被重新编程为可持续的治疗策略，可能会改善狼疮 病人的健康。

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.