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: 10320436
• 负责人: Joseph Edgar Craft
• 金额: $ 29.85万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320436
• 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.

项目概要（摘要） 系统性红斑狼疮（SLE，lupus）的特征是产生自身抗体， 组织损伤次级淋巴细胞B细胞滤泡和生发中心（GC）中的滤泡辅助性T（Tfh）细胞 器官对于B细胞增殖和存活、免疫球蛋白（IG）亲和选择以及 免疫接种和病原体攻击后记忆B和长寿浆细胞的发育。 自身反应性Tfh细胞和GC B细胞在SLE中发展并持续存在，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细胞的激活和维持机制在 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。 致病性自身抗体和随后的组织损伤，并在确定治疗干预。 活化T细胞核因子（NFAT）家族转录因子在T细胞活化时普遍活化， 细胞受体（TCR）信号传导。NFAT被磷酸酶钙调磷酸酶激活：在经典的NFAT信号传导中， 去磷酸化的NFAT易位到细胞核，并与其他转录因子，如 AP-1家族成员，以激活细胞因子（包括IL-2）以及其他可溶性和非可溶性细胞因子的基因转录。 细胞表面效应物。我们已经确定NFAT在Tfh细胞中以AP-1独立模式工作 在非自身免疫小鼠的病毒感染后激活，与其他T细胞群体不同， 我们认为，这种模式对Tfh细胞在GC环境中的独特功能至关重要。目前尚不清楚是否相同 发生在狼疮的异常持续GC反应中。 我们假设AP-1非依赖性NFAT信号传导对于Tfh细胞的发育和功能是必不可少的， 并且理解这种独特的NFAT信号传导模式将提供对Tfh细胞功能的深入了解， 狼疮伴持续B细胞帮助产生自身抗体。我们将解决我们的假设 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，当与患者调查一起分析时，它们的效用被放大。我们提出了两 目标。在目标1中，我们将在非自身免疫小鼠的Tfh细胞中询问NFAT信号传导，确定AP-1是否与Tfh细胞中的NFAT信号传导相关。 独立的NFAT信号传导对于Tfh细胞发育和功能是必需的和/或足够的，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细胞中的NFAT信号传导谱。这些信息将作为我们研究的重要比较， 狼疮Tfh细胞在aim 2.在后者中，我们将在小鼠Tfh细胞中研究失调的NFAT信号传导。 并研究钙调磷酸酶抑制对疾病起始的分子和细胞作用， 进展和器官损伤然后，我们将使用来自患者的Tfh细胞来测试我们发现的相关性。 关于SLE这些信息将使我们能够确定Tfh细胞信号通路是否在系统性 自身免疫，并剖析疾病的治疗干预的可能途径。

项目成果

CD4+ follicular regulatory T cells optimize the influenza virus-specific B cell response.

• DOI: 10.1084/jem.20200547
• 发表时间: 2021-03-01
• 期刊: The Journal of experimental medicine
• 作者: Lu Y;Jiang R;Freyn AW;Wang J;Strohmeier S;Lederer K;Locci M;Zhao H;Angeletti D;O'Connor KC;Kleinstein SH;Nachbagauer R;Craft J
• 通讯作者: Craft J

T Follicular Regulatory Cells: Choreographers of Productive Germinal Center Responses.

• DOI: 10.3389/fimmu.2021.679909
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Lu Y;Craft J
• 通讯作者: Craft J

Cutting Edge: IL-21 and Tissue-Specific Signals Instruct Tbet+CD11c+ B Cell Development following Viral Infection.

前沿：IL-21 和组织特异性信号指导病毒感染后 Tbet CD11c B 细胞的发育。

• DOI: 10.4049/jimmunol.2300027
• 发表时间: 2023
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Song,Wenzhi;Sanchez,GinaM;Mayer,DanielP;Blackburn,HollyN;Chernova,Irene;Flavell,RichardA;Weinstein,JasonS;Craft,Joe
• 通讯作者: Craft,Joe

HIF-1 regulates pathogenic cytotoxic T cells in lupus skin disease.

• DOI: 10.1172/jci.insight.166076
• 发表时间: 2023-08-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Little, Alicia J.;Chen, Ping-Min;Vesely, Matthew D.;Khan, Rahanna N.;Fiedler, Jacob;Garritano, James;Maisha, Fahrisa I.;Mcniff, Jennifer M.;Craft, Joe
• 通讯作者: Craft, Joe

T follicular helper cells in cancer, tertiary lymphoid structures, and beyond.

• DOI: 10.1016/j.smim.2023.101797
• 发表时间: 2023-06
• 期刊: Seminars in immunology
• 影响因子: 7.8
• 作者: Can Cui;J. Craft;Nikhil S. Joshi