Nuclear Receptors in B Cell Tolerance and Humoral Immune Responses

B 细胞耐受和体液免疫反应中的核受体

基本信息

批准号：
10626756
负责人：
JULIE ZIKHERMAN
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626756
关键词：
Acute Address Affinity Agonist Alleles Antibody Response Antigens Architecture Autoantibodies Autoimmune Autoimmune Diseases Autoimmunity B cell differentiation B cell repertoire B-Cell Activation B-Lymphocytes Bacterial Artificial Chromosomes Base Sequence Binding Biology Chronic Clone Cells Coupled DNA Binding Domain Data Defect Development Disease Enzyme-Linked Immunosorbent Assay Exhibits Family Family member Feedback Gene Expression Genes Genetic Transcription Goals Grant Immune Immune response Immunity Knowledge Ligands Lupus Lymphocyte Masks Mediating Modeling Molecular Multiple Sclerosis Mus NR4A2 gene Nuclear Hormone Receptors Nuclear Receptors Orphan Peripheral Play Process Radiation Chimera Reporter Reporting Repression Role Signal Transduction Stains Structure of germinal center of lymph node T-Lymphocyte Testing Therapeutic Vaccination Vaccines antagonist c-myc Genes expectation gene repression genetic approach genome-wide humoral immunity deficiency member novel novel therapeutics preservation programs recruit response restraint single-cell RNA sequencing small molecule transcription factor unpublished works

项目摘要

Project Summary/Abstract This proposal's long-term goal is to take advantage of the biology of the Nr4a family of orphan nuclear hormone receptors to selectively manipulate antigen-specific B cell responses. If successful, this could transform our approach to vaccination and treatment of immune-mediated diseases. Nr4a family members (Nur77, Nurr1, and Nor1) are encoded by three genes (Nr4a1-3, respectively) that are rapidly induced by antigen (Ag) stimulation in lymphocytes. Although they are thought to function as ligand- independent, constitutively active transcription factors, small molecule agonist and antagonist ligands have been developed, rendering them druggable. We have shown that a fluorescent reporter of Nr4a1 expression (Nur77- eGFP BAC Tg) scales with the intensity of Ag stimulation, and also correlates with self-reactivity in naturally occurring B cells in healthy mice and in three different BCR Tg models. We have recently shown that Nur77 curbs the survival and expansion of B cells in response to chronic and acute Ag stimulation, imposing a novel layer of B cell tolerance. Importantly, the Nr4a family harbor considerable structural homology in their DNA- binding domain and, as a result, exhibit profound functional redundancy in T cells, where they also play an important regulatory role. Such redundancy is likely highly relevant to their function in B cells (which predominantly express Nr4a1 and Nr4a3) yet has never been experimentally addressed. This represents a major gap in our knowledge that limits full therapeutic exploitation of these factors. Here we report that newly generated mice with B cell-specific deletion of Nr4a1 and Nr4a3 show a major break in B cell tolerance, including the development of spontaneous germinal centers and autoantibodies. These defects correlate with profound super-induction of novel target genes in response to Ag stimulation – including several genes required for recruitment of T cell help – that is largely masked when even one functional Nr4a allele remains. We therefore hypothesize that the Nr4a family mediates negative feedback downstream of Ag stimulation via transcriptional repression of key target genes. We propose that this serves two functions: (a) to restrain self-reactive clones that receive signal 1 (antigen) in the absence of signal 2 (co-stimulation), and (b) restrain immunodominant clones from monopolizing normal humoral immune responses, in order to preserve clonal diversity. In this grant, we propose: (1) To define the role of the Nr4a family in regulating central and peripheral B cell tolerance, and identify transcriptional mechanisms that mediate these functions in BCR Tg and naturally occurring self-reactive B cells. (2) To define the role of the Nr4a family in regulating B cell inter-clonal competition and clonal diversity during the primary T-dependent humoral immune response and its contribution to limiting immunodominance. (3) To define the role of the newly identified Nr4a target gene Batf in mediating these processes.

项目摘要/摘要该提议的长期目标是利用NR4A孤儿核马的生物学接收器选择性操纵抗原特异性B细胞反应。如果成功，这可能会改变我们的免疫介导疾病的疫苗接种和治疗方法。 NR4A家庭成员（NUR77，Nurr1和Nor1）由三个基因（NR4A1-3）编码为淋巴细胞中抗原（Ag）刺激迅速诱导。尽管它们被认为是配体的功能独立的，组成型活性的转录因子，小分子激动剂和拮抗剂配体已是开发，使它们可吸毒。我们已经表明，NR4A1表达的荧光记者（NUR77-- EGFP BAC TG）尺度与Ag刺激的强度，并且与自然的自反应性相关在健康小鼠和三种不同的BCR TG模型中发生B细胞。我们最近表明Nur77 遏制响应慢性和急性Ag刺激的B细胞的存活和扩展，施加了新型 B细胞耐受层。重要的是，NR4A家族在其DNA中具有相当大的结构同源性结合结构域，结果暴露了T细胞中的深刻功能冗余，它们也会发挥作用重要的监管角色。这种冗余可能与它们在B细胞中的功能高度相关（主要表达NR4A1和NR4A3），但从未实验。这代表在我们的知识中，主要的差距限制了对这些因素的完全治疗性开发。在这里，我们报告说，NR4A1和NR4A3的B细胞特异性缺失新生成的小鼠显示了一个重大突破在B细胞耐受性中，包括发育中心和自身抗体的发展。这些与AG刺激的反应，与新靶基因的深层超级诱导相关的缺陷与包括募集T细胞帮助所需的几个基因 - 当甚至一个功能性NR4A时，这在很大程度上被掩盖了等位基因仍然存在。因此，我们假设NR4A家族介导了Ag下游的负反馈通过关键靶基因的转录表示刺激。我们建议这有两个功能：（a）在没有信号2（共刺激）的情况下，限制接收信号1（抗原）的自反应性克隆，（b）为了保存克隆多样性。在这笔赠款中，我们建议：（1）定义NR4A家族在调节中心和外围B细胞耐受性中的作用，并确定转录机制介导了这些功能在BCR TG和自然发生的自我反应性B细胞中。（2）定义NR4A家族在调节B细胞之间的竞争和克隆多样性中的作用主要的T依赖性体液免疫响应及其对限制免疫力的贡献。（3）定义新鉴定的NR4A靶基因BATF在介导这些过程中的作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.

DOI：
10.1038/s41589-021-00852-0
发表时间：
2021-11
期刊：
Nature chemical biology
影响因子：
14.8
作者：
Feldman HC;Ghosh R;Auyeung VC;Mueller JL;Kim JH;Potter ZE;Vidadala VN;Perera BGK;Olivier A;Backes BJ;Zikherman J;Papa FR;Maly DJ
通讯作者：
Maly DJ

Many Achilles' heels of B and T cell tolerance.