Targeting follicular helper CD4 T cells in SLE

靶向 SLE 中的滤泡辅助 CD4 T 细胞

• 批准号: 9244330
• 负责人: Laurence Morel
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9244330
• 关键词: Adoptive Transfer; Affinity; Anatomy; Antibodies; Autoantibodies; BCL6 gene; CD4 Positive T Lymphocytes; Cell model; Cell physiology; Cells; Cellular Immunology; Cellular Metabolic Process; Data; Development; Disease; Flu virus; Frequencies; Gene Expression; Gene Expression Profile; Glucose; Glycolysis; Glycolysis Inhibition; Goals; Health; Helper-Inducer T-Lymphocyte; Human; Humoral Immunities; Immunization; Immunize; Immunoglobulin Class Switching; Immunophenotyping; In Vitro; Location; Lupus; Maintenance; Metabolic; Metabolism; Metformin; Modeling; Molecular; Molecular Immunology; Mus; Pathogenicity; Patients; Population; Production; Publishing; Reaction; Reporting; Resistance; Role; SLEB1 gene; SLEB2 gene; SLEB3 gene; Severity of illness; Supporting Cell; Susceptibility Gene; System; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Therapeutic Intervention; Tissues; Virus; base; flu; glucose analog; glucose metabolism; improved; inhibitor/antagonist; lupus prone mice; metabolic profile; mouse model; novel; pathogen; response; transcription factor

Project Summary/Abstract This proposal intends to characterize Tfh cells, a population that is critical for disease development and maintenance in SLE and test the novel hypothesis that SLE-Tfh are uniquely sensitive to metabolic inhibition, a feature that can be exploited to therapeutic intervention. The scientific premise of this proposal is based on three lines of evidence: 1. The necessary role of Tfh cells for the production of pathogenic autoAbs in lupus has been well-established in SLE patients and mouse models; 2. Tfh cells induced by immunization are metabolically quiescent, a fact that we have confirmed showing that they are not affected by glucose inhibitors in lupus-prone and control mice; and 3. We have strong preliminary data showing that SLE-Tfh cells from four different mouse models of lupus are sensitive to glucose. We propose the hypothesis that spontaneous Tfh cells supporting the production of autoAbs (SLE-Tfh) have a different metabolism than Tfh cells providing protective humoral immunity against pathogens (TD-Tfh) in either lupus or normal mice. Based on similarities of CD4+ T cell functions and metabolism in lupus-prone mice and SLE patients, we also hypothesize that the expanded Tfh cells in SLE patients also have a different metabolism than that of health controls (HCs). Consequently, we predict that targeting Tfh cellular metabolism provides an effective approach to treat lupus without compromising the patients’ protection against TD- pathogens. We propose to test these hypotheses using cellular and molecular immunology approaches in mouse models as well as with human PBLs with the three following specific aims 1. To define the molecular and metabolic signatures of SLE-Tfh as compared to TD-Tfh cells elicited by TD-dependent Ags (PR8 flu virus and NP-OVA) in lupus mice and B6 controls. The immunophenotypes, anatomical location, gene expression, and metabolic profile of spontaneous Tfh cells in TC and B6.lpr mice will be compared to that of flu-specific I-A(b) NP-tetramer positive Tfh cells in TC, B6.lpr and B6 mice infected with PR8 virus. In addition to these polyclonal T cell models, we will use an adoptive transfer model of OVA-specific OT-II T cells carrying the Sle1 lupus susceptibility allele that favors the expansion of Tfh cells (9) into NP-OVA immunized mice (10). This aim will define the functional differences between TD-Tfh and SLE-Tfh cells in two models of lupus and with two different TD-immunizations. 2. To define the response of SLE-Tfh and TD-Tfh cells to glucose inhibition in the mouse. Using the same experimental systems as in SA1, we will compare the responses of SLE-Tfh cells and TD-Tfh cells to glucose inhibition in mice treated with 2DG, a glucose analog that blocks the first reaction of glycolysis. 3. To compare the molecular and metabolic signatures of circulating cTfh cells in SLE patients and HCs, as well as their response to metformin. We hypothesize that the expansion of cTfh cells in SLE patients is largely driven by autoAgs, and that SLE-cTfh cells share functional signatures with murine SLE-Tfh cells. On the other hand, cTfh cells from HCs have been largely induced by TD-Ags, and HC-cTfh cells should overlap with murine TD-Tfh cells. We will compare the immunophenotypes and gene expression of these two types of Tfh cells, as well as their response to the metabolic inhibitor metformin in vitro. Our first goal is to advance our understanding of SLE-Tfh cells, and ultimately to advance the treatment of lupus, based on discrete, achievable goals focusing on one cell population. This project will advance our understanding of disease mechanisms, and yield results with a high translational potential.

项目总结/摘要 该提案旨在表征Tfh细胞，这是一种对疾病发展至关重要的细胞群， 维持SLE，并测试新的假设，即SLE-Tfh是唯一敏感的代谢抑制， 这一特点可以用于治疗干预。这一建议的科学前提是基于 证据有三条：1. Tfh细胞在狼疮致病性自身抗体产生中的必要作用 已在SLE患者和小鼠模型中得到充分确立; 2.免疫诱导的Tfh细胞是 代谢静止，我们已经证实的事实表明，它们不受葡萄糖抑制剂的影响， 在狼疮易感小鼠和对照小鼠中;和3.我们有强有力的初步数据显示，来自四个国家的SLE-Tfh细胞 不同的狼疮小鼠模型对葡萄糖敏感。 我们提出了一个假设，即支持自身抗体产生的自发性Tfh细胞（SLE-Tfh）具有一种免疫调节作用， 与Tfh细胞不同的代谢，提供针对病原体的保护性体液免疫（TD-Tfh）， 狼疮或正常小鼠。基于狼疮易感小鼠中CD 4 + T细胞功能和代谢的相似性， 对于SLE患者，我们还假设SLE患者中扩增的Tfh细胞也具有不同的增殖能力。 健康对照组（HC）。因此，我们预测靶向Tfh细胞代谢， 提供了一种有效的方法来治疗狼疮，而不损害患者对TD的保护， 病原体我们建议使用细胞和分子免疫学方法来测试这些假设， 小鼠模型以及人PBL，具有以下三个特定目的 1.与TD-Tfh细胞相比，确定SLE-Tfh的分子和代谢特征 在狼疮小鼠和B6对照中由TD依赖性Ag（PR 8流感病毒和NP-OVA）引起。的 免疫表型，解剖位置，基因表达，和自发Tfh细胞的代谢谱， 将TC和B6. lpr小鼠与TC、B6. lpr中流感特异性I-A（B）NP-四聚体阳性Tfh细胞的小鼠进行比较。 和感染PR 8病毒的B6小鼠。除了这些多克隆T细胞模型之外，我们还将使用过继性T细胞模型。 携带Sle 1狼疮易感性等位基因的OVA特异性OT-II T细胞转移模型， 将Tfh细胞（9）扩增到NP-OVA免疫的小鼠（10）中。这一目标将确定功能差异 TD-Tfh和SLE-Tfh细胞在两种狼疮模型和两种不同TD免疫中的差异。 2.确定小鼠中SLE-Tfh和TD-Tfh细胞对葡萄糖抑制的反应。使用 在与SA 1相同的实验系统中，我们将比较SLE-Tfh细胞和TD-Tfh细胞对 用2DG（一种阻断糖酵解第一反应的葡萄糖类似物）处理的小鼠中的葡萄糖抑制。 3.比较SLE患者循环cTfh细胞的分子和代谢特征， HC及其对二甲双胍的反应。我们假设SLE中cTfh细胞的扩增 患者主要由autoAg驱动，并且SLE-cTfh细胞与鼠SLE-Tfh共享功能特征 细胞另一方面，来自HC的cTfh细胞已经在很大程度上被TD-Ags诱导，并且HC-cTfh细胞应该 与鼠TD-Tfh细胞重叠。我们将比较两者的免疫表型和基因表达 Tfh细胞的类型，以及它们对体外代谢抑制剂二甲双胍的反应。 我们的第一个目标是促进我们对SLE-Tfh细胞的理解，并最终促进SLE-Tfh细胞的治疗。 狼疮，基于离散的，可实现的目标，专注于一个细胞群。该项目将推动我们的 了解疾病机制，并产生具有高翻译潜力的结果。