Determinants of follicular helper T cell expansion in lupus

项目概要/摘要 滤泡辅助细胞（Tfh）及其相关亚群的扩增与人类淋巴结转移的严重程度相关。 狼疮疾病，并由所有狼疮易感小鼠模型共享。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，本建议的目的是对这些机制提供新的认识， 负责狼疮中Tfh细胞扩增的细胞， 从狼疮的B6.Sle1.Sle2.Sle3三重同源（TC）鼠模型获得的数据。因此我们 已经确定了调节狼疮Tfh细胞扩增的遗传以及微生物和代谢决定因素。 将狼疮小鼠肠道菌群扰动转移到小鼠宿主中对Tfh细胞至关重要 扩张.此外，色氨酸（Trp）代谢的改变也增强了Tfh细胞的扩增， 通过控制饮食中的Trp水平来降低。最后，用2-脱氧-D-葡萄糖（2DG）抑制糖酵解， 或用6-重氮-5-氧代-L-正亮氨酸（DON）进行的氨解在功能上减少了狼疮Tfh细胞的分化。 我们的假设是，与狼疮有关的Tfh细胞的扩增整合了易感基因的线索， 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细胞具有新的代谢基因特征，可能驱动自身反应性Tfh细胞扩增， 由独特的代谢流控制因此，我们建议将Tfh细胞转录组的分析和 代谢组学响应于上述线索的变化，作为阐明相关分子的手段。 机制，单独或组合，影响狼疮中Tfh细胞的命运。我们还建议调查 功能上影响Tfh细胞的遗传和环境决定因素对两个B细胞亚群的影响， CD 11 c +Tbet+ B细胞（ABC）和伊加+ B细胞。为此，提出了以下具体目标。1.到 探索狼疮易感基因调节Tfh细胞转录组的机制， 在两个不相关的TC和（NZW x BXSB.Yaa）F1狼疮模型中的代谢组。2.确定以下方面的影响 环境因素对TC小鼠Tfh转录组和代谢组的影响。和3.为了阐明 狼疮患者中Tfh细胞扩增的相关机制。从这些机制中获得的结果 实验将是第一次深入调查Tfh细胞扩增由环境和遗传指导 决定因素，这可能是一个可持续的治疗策略，也许改善狼疮重新编程 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.