Follicular Helper T Cell Function in Autoimmunity

滤泡辅助 T 细胞在自身免疫中的功能

• 批准号: 10061557
• 负责人: Joseph Edgar Craft
• 金额: $ 32.17万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-10 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10061557
• 关键词: Address; Affinity; Antibody Formation; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; B Cell Proliferation; B-Lymphocytes; Biology; Calcineurin; Calcineurin inhibitor; Cell Nucleus; Cell Survival; Cell physiology; Cell surface; Cells; Choristoma; Clinical; Collaborations; Development; Disease; Dissection; Environment; Exhibits; FK506; Family; Family member; Generations; Genetic Transcription; Goals; Graft Rejection; Helper-Inducer T-Lymphocyte; Human; Immunization; Immunoglobulins; Interferon Type I; Interleukin-2; Interruption; Investigation; Knowledge; Lupus; Lupus Nephritis; Maintenance; Memory; Memory B-Lymphocyte; Metabolic; Modeling; Molecular; Mus; Organ; Pathogenesis; Pathway interactions; Patients; Physiological; Plasma Cells; Play; Population; Production; Receptor Signaling; Role; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; T cell response; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Tacrolimus; Testing; Therapeutic; Therapeutic Intervention; Transcription Factor AP-1; Vaccination; Virus Diseases; autoreactive B cell; autoreactivity; calcineurin phosphatase; clinical investigation; cytokine; flexibility; insight; interest; mouse model; novel; nuclear factors of activated T-cells; pathogen; pathogenic autoantibodies; prevent; response; secondary lymphoid organ; side effect; systemic autoimmunity; tissue injury; tool; transcription factor

PROJECT SUMMARY (ABSTRACT) Systemic lupus erythematosus (SLE, lupus) is characterized by the generation of autoantibodies that promote tissue injury. Follicular helper T (Tfh) cells in B-cell follicles and germinal centers (GCs) of secondary lymphoid organs are necessary for B-cell proliferation and survival, immunoglobulin (Ig) affinity selection, and development of memory B and long-lived plasma cells following vaccination and pathogen challenge. Autoreactive Tfh cells and GC B cells develop and persist in SLE, with generation of autoreactive memory B cells and autoantibody-producing plasma cells. The mechanism(s) of activation and maintenance of Tfh cells in lupus, and how they in turn promote autoreactive B cell responses, are critical to understanding the generation of pathogenic autoantibodies and subsequent tissue injury, and in determining therapeutic intervention. The Nuclear Factor of Activated T cells (NFAT) family of transcription factors is ubiquitously activated upon T cell receptor (TCR) signaling. NFAT is activated by the phosphatase calcineurin: in canonical NFAT signaling, dephosphorylated NFAT translocates to the nucleus and cooperates with other transcription factors, such as AP-1 family members, to activate gene transcription of cytokines, including IL-2, as well as of other soluble and cell-surface effectors. We have determined that NFAT operates in an AP-1 independent mode in Tfh cells activated upon viral infection of non-autoimmune mice, distinct from that of other T cell populations, a signaling mode we believe essential to the unique function of Tfh cells in the GC environment. It is not known if the same occurs in the abnormal, persistent GC response in lupus. We hypothesize that AP-1 independent NFAT signaling is essential for development and function of Tfh cells, and that understanding this unique mode of NFAT signaling will provide insight into the Tfh-cell function in lupus with persistence of B cell help necessary for autoantibody production. We will address our hypothesis using murine models and cells from lupus patients. Mouse models are excellent tools for studies of disease pathogenesis; yet, their utility is magnified when analyzed alongside investigation of patients. We propose two aims. In aim 1, we will interrogate NFAT signaling in Tfh cells in non-autoimmune mice, determining if AP-1 independent NFAT signaling is necessary and/or sufficient for Tfh cell development and function, and identifying the downstream effector pathways of NFAT in Tfh cells, with the goal to develop a comprehensive profile of NFAT signaling in Tfh cells. This information will serve as an essential comparator to our studies of lupus Tfh cells in aim 2. In the latter, we will interrogate NFAT signaling in dysregulated Tfh cells in murine lupus and investigate the molecular and cellular effects of calcineurin inhibition on disease initiation, progression, and organ damage. We will then test the relevance of our findings using Tfh cells from patients with SLE. This information will enable us to determine if Tfh-cell signaling pathways are altered in systemic autoimmunity, and dissect possible avenues of therapeutic intervention in disease.

项目摘要(摘要) 系统性红斑狼疮(SLE，狼疮)的特征是产生促进 组织损伤。次级淋巴B细胞滤泡和生发中心的滤泡辅助性T细胞 器官是B细胞增殖和生存、免疫球蛋白(Ig)亲和力选择和 接种疫苗和病原体攻击后记忆B和长寿命浆细胞的发展。 自身反应性Tfh细胞和GC B细胞在SLE中发展和持续存在，并产生自身反应性记忆B 细胞和产生自身抗体的浆细胞。TFH细胞激活和维持的机制(S) 狼疮，以及它们如何反过来促进自身反应性B细胞反应，对于理解狼疮的产生至关重要 病原性自身抗体和随后的组织损伤，以及确定治疗干预措施。 活化T细胞核因子(NFAT)家族转录因子在T细胞上被广泛激活 细胞受体(TCR)信号传递。NFAT由磷酸酶钙调神经磷酸酶激活：在典型的NFAT信号中， 去磷酸化的NFAT转位到细胞核，并与其他转录因子合作，如 AP-1家族成员，激活包括IL-2在内的细胞因子的基因转录，以及其他可溶性和 细胞表面效应器。我们已经确定NFAT在TFH细胞中以AP-1独立模式工作 在病毒感染非自身免疫性小鼠时被激活，与其他T细胞群不同，信号转导 我们认为TFH细胞在GC环境中的独特功能所必需的模式。目前还不知道是否相同 发生在狼疮患者异常的、持续的GC反应中。 我们假设AP-1非依赖的NFAT信号对TFH细胞的发育和功能是必不可少的， 了解NFAT信号的这种独特模式将有助于深入了解TFH-cell在 B细胞持续存在的狼疮有助于自身抗体的产生。我们将阐述我们的假设 使用小鼠模型和狼疮患者的细胞。小鼠模型是研究疾病的极好工具 发病机制；然而，当结合对患者的调查进行分析时，它们的实用性被放大。我们建议两个 目标。在目标1中，我们将询问非自身免疫小鼠Tfh细胞中的NFAT信号，确定AP-1 独立的NFAT信号对于TFH细胞的发育和功能是必要的和/或充分的，并且 确定TFH细胞中NFAT的下游效应通路，目标是开发一种全面的 TFH细胞中NFAT信号的研究概况。这些信息将成为我们研究 在AIM 2中，我们将询问调节异常的小鼠Tfh细胞中的NFAT信号转导 并研究钙调神经磷酸酶抑制疾病启动的分子和细胞效应， 进展和器官损伤。然后，我们将使用患者的TFH细胞来测试我们的发现的相关性 系统性红斑狼疮。这一信息将使我们能够确定TFH细胞信号通路是否在系统性改变 自身免疫，并剖析疾病治疗干预的可能途径。