IL-27-producing B cells in the antibody response

抗体反应中产生 IL-27 的 B 细胞

• 批准号: 10211938
• 负责人: Zhenming Xu
• 金额: $ 44.32万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/10211938
• 关键词: 2019-nCoV; Acquired Immunodeficiency Syndrome; Address; Affinity; Antibodies; Antibody Response; Antigens; Antiviral Agents; 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 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; vector; virtual; 2019-nCoV; Acquired Immunodeficiency Syndrome; Address; Affinity; Antibodies; Antibody Response; Antigens; Antiviral Agents; 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 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; vector; virtual

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 - 抗体反应中产生的IL-27生产B细胞 建立在我们的新发现的基础上，即B细胞可以被诱导表达高水平的IL-27（IL27P28/EBI3异二聚体）， 该建议将探讨IL-27和IL-27产生B的作用的基础分子和细胞机制 类切换抗体（AB）反应中的细胞（B-27细胞）。正如我们所争论的那样，B-27细胞塑造了幅度 和T依赖性AB反应的质量，包括病毒感染引起的AB反应。正如我们也认为，他们 这样做是“助手” B细胞以增强其目标“效应子” B细胞的功能，即对抗原响应的功能 并分化为产生IgG的细胞。这种类切换的ABS包括直接中和的IgG1 病毒，人IgG3和小鼠IgG2A/IgG2C（IgG2A），它们具有额外的抗病毒效应功能。 由于归纳的先天和适应性免疫受体信号的独特要求，B-27 细胞在策略上定位以介导TLR配体在增强AB反应中的潜在影响。 我们假设B-27细胞的诱导方式取决于转录因子BATF3，并且 通过与IFNG合作以促进扩散，生存和完全差异来优化AB响应 产生IgG的B细胞。这是基于我们引人入胜的初步数据，表明：（i）是一个重要的 IL-27的来源，诱导B细胞在TLR配体启动后产生IL-27，然后通过TFH刺激 细胞刺激CD154和IL-21； （ii）在IL27P28，EBI3或BATF3中具有B细胞特异性缺陷的小鼠在 IL-27产生和特定的IgG2A响应； （iii）IL-27激活统计，将CSR引导到IGG2A并促进 体外CD154和IL-21刺激的B细胞中的存活和浆细胞分化； （iv）IL-27和IFNG 同时增强B细胞生长和体外分化，相反，IL-27R和IFNGR缺乏症合并 在B细胞中，消除了特定的IgG2a反应，并在体内显着损害IgG1反应。 为了检验我们的假设，我们将（AIM 1）表征在TG（IL27P28-GFP）报道小鼠中诱导的B-27细胞 离甲酸病毒（VV）感染，该病毒也被用作多种疫苗的载体，或与免疫接种 共轭抗抗NP-CGG与明矾和TLR配体LPS混合；并确定B-27细胞的合作 特定IgG响应中的IFNG和潜在效应子B细胞增殖，存活，CSR/SHM，浆细胞 和记忆B细胞分化。我们还将（AIM 2）解决BATF3角色的基础机制 在IL27P28中，通过在体外鉴定其在IL27P28基因座和伴侣转录因子中的顺式元素来诱导； 和分析B细胞BATF3及其对B-27细胞产生和AB对VV感染的影响的影响 和NP-CGG/明矾/LPS体内。最后，我们将（AIM 3）分析B细胞IL-27R和IFNGR的合作 优化效应子B细胞生长和分化的信号响应VV感染和刺激 与CD154和IL-21体外；并解决基本机制，重点关注其协同作用 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 将对对IgG对病毒感染和疫苗发育的反应的理解产生持续的影响。