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（由申请方提供）：T滤泡辅助细胞（Tfh细胞）是一种新的效应细胞亚群，其特征在于存在于生殖中心、产生IL-21及其作为B细胞和抗体（IgG）产生辅助细胞的重要作用。然而，与其他T辅助细胞亚群不同，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，并且可以失去其表型，如果存在正确的环境，不同的效应细胞可以成为Tfh细胞。导致这种可塑性的因素仍然未知。我们已经表明，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，是一种独特的因子，它是诱导幼稚和记忆CD 4 T细胞产生IL-21所必需和足够的。我们的初步研究表明，IL-6还能够在效应Th 1、Th 2和Th 17细胞活化过程中增强IL-21的产生。 我们还表明，IL-6通过间接作用于CD 4 T细胞，诱导其IL-21产生，并且该IL-21作用于B细胞来增强抗体应答。我们提出，IL-6是一个主要的先天性免疫因子，有助于Tfh细胞的可塑性，从而通过紧张性调节IL-21在CD 4 T细胞中的表达，而没有一个完整的承诺抗体的生产。我们还提出，IL-6引起的可塑性是通过其对两个独立信号通路的作用介导的，1）STAT 3，调节线粒体代谢，和2）C/EBP 2，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应答与CD 4和B细胞应答整合的关键。我们将确定1）IL-6通过在初始、效应和记忆CD 4 T细胞中张力诱导IL-21产生对Tfh细胞可塑性的贡献（Aim 1），2）STAT 3和C/EBP 2转录因子对IL-6介导的CD 4 Tfh细胞可塑性的贡献（Aim 2），3）IL-6通过促进记忆性CD 4 T细胞转化为Tfh细胞在抗病毒记忆反应中的保护作用（目的3）。