IL-6: an innate immune regulator for the plasticity of Tfh cells

IL-6：Tfh 细胞可塑性的先天免疫调节剂

• 批准号: 8434542
• 负责人: Mercedes Rincon
• 金额: $ 44.13万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434542
• 关键词: Address; Affect; Antibodies; Antibody Formation; Antigens; Antiviral Agents; B-Lymphocytes; Binding; Biological Response Modifiers; CD4 Positive T Lymphocytes; Cell physiology; Cells; Commit; Development; Effector Cell; Electron Transport; Enhancing Antibodies; Environment; Gene Expression Regulation; Generations; Genes; Genetic Polymorphism; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; Immune; Immune response; Immunoglobulin G; In Vitro; Individual; Infection; Inflammatory; Influenza; Institutes; Interleukin-17; Interleukin-6; Knockout Mice; Lead; Mediating; Memory; Metabolism; Mitochondria; Modeling; Mus; Nucleic Acid Regulatory Sequences; Pathway interactions; Phenotype; Physiological; Play; Population; Process; Production; Recurrence; Reporting; Role; STAT3 gene; Signal Pathway; Source; Structure of germinal center of lymph node; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Transgenic Mice; Universities; Vaccines; Vermont; Viral; Viral Vaccines; Virus; Virus Diseases; allergic airway inflammation; cytokine; design; in vivo; in vivo Model; influenza virus vaccine; influenzavirus; interest; memory CD4 T lymphocyte; neutralizing antibody; prevent; promoter; response; secondary infection; selective expression; transcription factor

DESCRIPTION (provided by applicant): T follicular helper cells (Tfh cells) are a new subset of effector cells characterized by their presence in germinal centers, the production of IL-21 and their essential role as helper of B cells and antibody (IgG) production. However, unlike other T helper subsets, a certain degree of plasticity seems to be present in Tfh cells since they are not fully committed and can lose their phenotype, and different effector cells can become Tfh cells if the right environment is present. The factor/s contributing to this plasticity remain unknown. We have shown that IL-6, a cytokine derived by a number of innate immune cells and non-hematopoietic cells, is a unique factor necessary and sufficient to induce IL-21 production in naove and memory CD4 T cells. Our preliminary studies indicate the IL-6 is also able to enhance IL-21 production during the activation of effector Th1, Th2 and Th17 cells. We have also shown that IL-6 enhances antibody responses by indirectly acting on CD4 T cells, inducing their IL-21 production, and this IL-21 acting on B cells. We propose that IL-6 is a major innate immune factor that contributes to the plasticity of Tfh cells and thereby Ab production by tonically regulating IL-21 expression in CD4 T cells without a full commitment. We also propose that the plasticity caused by IL-6 is mediated by its effect on two independent signaling pathways, 1) STAT3, modulating mitochondrial metabolism, and 2) C/EBP2, providing selective expression of IL-21. IL-6-mediated plasticity may be key in the integration of the innate immune response with CD4 and B cell responses. We will determine 1) the contribution of IL-6 to the plasticity of Tfh cells by tonically inducing IL-21 production in naive, effector and memory CD4 T cells (Aim 1), 2) the contribution of STAT3 and C/EBP2 transcription factors to the IL-6 mediated plasticity of CD4 Tfh cells (Aim 2), 3) the role of IL-6 in protective antiviral memory response by promoting memory CD4 T cells to become Tfh cells (Aim 3).

描述（由申请人提供）：滤泡辅助性T细胞（Tfh细胞）是一种新的效应细胞亚群，其特征在于它们存在于生发中心、产生IL-21以及它们作为B细胞和抗体（IgG）产生的辅助者的重要作用。然而，与其他 T 辅助亚群不同，Tfh 细胞似乎存在一定程度的可塑性，因为它们没有完全定型，可能会失去其表型，并且如果存在合适的环境，不同的效应细胞可以成为 Tfh 细胞。造成这种可塑性的因素仍然未知。我们已经证明，IL-6（一种由许多先天免疫细胞和非造血细胞衍生的细胞因子）是诱导幼稚和记忆 CD4 T 细胞产生 IL-21 所必需且充分的独特因子。我们的初步研究表明，IL-6 还能够在效应 Th1、Th2 和 Th17 细胞激活过程中增强 IL-21 的产生。 我们还表明，IL-6 通过间接作用于 CD4 T 细胞，诱导其产生 IL-21，而这种 IL-21 作用于 B 细胞，从而增强抗体反应。我们认为 IL-6 是一种主要的先天免疫因子，有助于 Tfh 细胞的可塑性，从而通过强调调节 CD4 T 细胞中 IL-21 的表达来产生抗体，而无需完全承诺。我们还提出，IL-6 引起的可塑性是由其对两条独立信号通路的影响介导的，1) STAT3，调节线粒体代谢，2) C/EBP2，提供 IL-21 的选择性表达。 IL-6 介导的可塑性可能是先天免疫反应与 CD4 和 B 细胞反应整合的关键。我们将确定 1) IL-6 通过在初始、效应和记忆 CD4 T 细胞中强效诱导 IL-21 产生来确定 IL-6 对 Tfh 细胞可塑性的贡献（目标 1），2) STAT3 和 C/EBP2 转录因子对 IL-6 介导的 CD4 Tfh 细胞可塑性的贡献（目标 2），3) IL-6 通过促进记忆 CD4 T 细胞成为保护性抗病毒记忆反应的作用。 Tfh 细胞（目标 3）。