IL-27-producing B cells in the antibody response

抗体反应中产生 IL-27 的 B 细胞

基本信息

批准号：
10338194
负责人：
Zhenming Xu
金额：
$ 44.49万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-02 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338194
关键词：
2019-nCoV Acquired Immunodeficiency Syndrome Address Affinity Antibodies Antibody Response Antigens B Cell Proliferation B cell differentiation B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Bacterial Infections Binding Biological COVID-19 COVID-19 vaccine Cell Shape Cells Clinical Trials Data Development Differentiation and Growth Diphtheria Disease Effector Cell Elements Gene Expression Generations Genetic Recombination Genetic Transcription HIV HIV vaccine Haptens Helper-Inducer T-Lymphocyte Human IL6ST gene IgG1 IgG3 Immune Immunization Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Somatic Hypermutation Immunologic Receptors Impairment In Vitro Infection Infectious Agent Intervention Knowledge Ligands Malaria Measles Mediating Medical Memory B-Lymphocyte Modeling Molecular Mumps Mus Nature Output Plague Plasma Cells Poliomyelitis Positioning Attribute Process Production Public Health Practice Receptor Signaling Recording of previous events Regulation Reporter Research Role Signal Transduction Smallpox Smallpox Vaccine Source Stimulus Structure of germinal center of lymph node TNFSF5 gene Testing Tetanus Vaccines Vaccinia virus Viral Viral Antibodies Viral Vaccines Virus Virus Diseases acute infection aluminum sulfate base chronic infection cytokine in vivo neutralizing antibody novel plasma cell differentiation receptor response success synergism tool transcription factor vaccine development vaccine efficacy vaccine strategy vector virtual

项目摘要

PROJECT SUMMARY – IL-27-producing B cells in the antibody response Built on our novel findings that B cells can be induced to express high levels of IL-27 (IL27p28/EBI3 heterodimer), this proposal will explore molecular and cellular mechanisms underlying the role of IL-27 and IL-27-producing B cells (B-27 cells) in class-switched antibody (Ab) responses. As we contend, B-27 cells shape the magnitude and quality of T-dependent Ab responses, including those elicited by viral infections. As we also contend, they do so as “helper” B cells to enhance the function of their target “effector” B cells, i.e., those responding to antigens and differentiating into IgG-producing cells. Such class-switched Abs include IgG1, which directly neutralizes virus, and human IgG3 and mouse IgG2a/IgG2c (IgG2a), which have additional anti-viral effector functions. Owing to the unique requirement of both innate and adaptive immune receptor signals for their induction, B-27 cells are strategically positioned to mediate the potent effect of TLR ligands in boosting the Ab response. We hypothesize that B-27 cells are induced in a manner dependent on transcription factor BATF3, and optimize the Ab response by cooperating with IFNg to promote proliferation, survival and full differentiation of IgG-producing B cells. This is based on our compelling preliminary data indicating that: (i) as an important source of IL-27, B cells are induced to produce IL-27 after priming by TLR ligands and then stimulation by Tfh cell stimuli CD154 and IL-21; (ii) mice with B cell-specific deficiency in Il27p28, Ebi3 or Batf3 are impaired in IL-27 production and specific IgG2a responses; (iii) IL-27 activates STATs, directs CSR to IgG2a and promotes survival and plasma cell differentiation in B cells stimulated by CD154 and IL-21 in vitro; and (iv) IL-27 and IFNg together boost B cell growth and differentiation in vitro, and, conversely, combined IL-27R and IFNgR deficiency in B cells abrogates specific IgG2a responses and significantly impairs IgG1 responses in vivo. To test our hypothesis, we will (Aim 1) characterize B-27 cells induced in Tg(Il27p28-Gfp) reporter mice upon infection by vaccinia virus (VV), which is also used as a vector of a variety of vaccines, or immunization with conjugated hapten NP-CGG mixed with alum and TLR ligand LPS; and determine the cooperation of B-27 cells with IFNg in specific IgG responses and underlying effector B cell proliferation, survival, CSR/SHM, plasma cell and memory B cell differentiation. We will also (Aim 2) address the mechanisms underlying the role of BATF3 in Il27p28 induction by identifying its cis-elements in the Il27p28 locus and partner transcription factors in vitro; and analyze induction of B cell BATF3 and its impact on B-27 cell generation and Ab responses to VV infection and NP-CGG/alum/LPS in vivo. Finally, we will (Aim 3) analyze the cooperation of B-cell IL-27R and IFNgR signals in optimizing effector B cell growth and differentiation in response to VV infection in vivo and stimulation with CD154 and IL-21 in vitro; and address the underlying mechanisms, focusing on their synergy in regulating STAT signal outputs and gene expression. By unveiling the mechanisms and function of B-27 cells, our studies will have a sustained impact on the understanding of IgG responses to viral infections and vaccine development.

项目摘要 – 抗体反应中产生 IL-27 的 B 细胞基于我们的新发现，即 B 细胞可以被诱导表达高水平的 IL-27（IL27p28/EBI3 异二聚体），该提案将探讨 IL-27 和产生 IL-27 的 B 作用的分子和细胞机制正如我们所说，B-27 细胞决定了类别转换抗体 (Ab) 反应的大小。以及 T 依赖性抗体反应的质量，包括由病毒感染引起的反应。作为“辅助”B 细胞来增强其目标“效应”B 细胞（即对抗原做出反应的细胞）的功能并分化为产生 IgG 的细胞，此类类别转换的抗体包括直接中和的 IgG1。病毒、人 IgG3 和小鼠 IgG2a/IgG2c (IgG2a)，具有额外的抗病毒效应功能。由于先天性和适应性免疫受体信号对其诱导的独特要求，B-27 细胞的战略定位是介导 TLR 配体在增强抗体反应方面的有效作用。我们见证了 B-27 细胞以依赖于转录因子 BATF3 的方式被诱导，并且通过与 IFNg 配合优化抗体反应，促进细胞增殖、存活和完全分化产生 IgG 的 B 细胞基于我们令人信服的初步数据，表明：(i) 作为一种重要的细胞。 IL-27 的来源，B 细胞在 TLR 配体引发和 Tfh 刺激后被诱导产生 IL-27 细胞刺激 CD154 和 IL-21；(ii) Il27p28、Ebi3 或 Batf3 B 细胞特异性缺陷的小鼠在 IL-27 产生和特异性 IgG2a 反应；(iii) IL-27 激活 STAT，将 CSR 引导至 IgG2a 并促进 CD154 和 IL-21 体外刺激的 B 细胞的存活和浆细胞分化；以及 (iv) IL-27 和 IFNg 共同促进 B 细胞体外生长和分化，相反，IL-27R 和 IFNgR 联合缺乏 B 细胞中的 IgG2a 消除了特异性 IgG2a 反应，并显着削弱了体内 IgG1 反应。为了检验我们的假设，我们将（目标 1）表征 Tg(Il27p28-Gfp) 报告小鼠中诱导的 B-27 细胞痘苗病毒（VV）感染，痘苗病毒也用作多种疫苗的载体，或用疫苗进行免疫缀合半抗原NP-CGG与明矾和TLR配体LPS混合并确定B-27细胞的配合； IFNg 参与特异性 IgG 反应和潜在效应 B 细胞增殖、存活、CSR/SHM、浆细胞我们还将（目标 2）探讨 BATF3 作用的潜在机制。通过在体外鉴定 Il27p28 基因座中的顺式元件和伙伴转录因子来进行 Il27p28 诱导；并分析 B 细胞 BATF3 的诱导及其对 B-27 细胞生成和对 VV 感染的 Ab 反应的影响最后，我们将（目标 3）分析 B 细胞 IL-27R 和 IFNgR 的配合。优化效应 B 细胞生长和分化以响应体内 VV 感染和刺激的信号 CD154 和 IL-21 的体外研究；并探讨其潜在机制，重点关注它们在调节方面的协同作用 STAT 信号输出和基因表达通过揭示 B-27 细胞的机制和功能，我们的研究将对理解 IgG 对病毒感染的反应和疫苗开发产生持续影响。