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

基本信息

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
项目类别：
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

项目摘要

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）：T卵泡辅助细胞（TFH细胞）是效应细胞的一个新的子集，其特征是它们在生发中心的存在，IL-21的产生以及它们作为B细胞和抗体（IgG）的重要作用（IgG）生产。但是，与其他T辅助子集不同，TFH细胞中似乎存在一定程度的可塑性，因为它们尚未完全投入，并且可能失去表型，并且如果存在正确的环境，则不同的效应细胞可能会变成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是由许多先天免疫细胞和非杂型细胞得出的细胞因子，是诱导NAOVE和记忆CD4 T细胞中IL-21产生的独特因素。我们的初步研究表明，IL-6在效应子Th1，Th2和Th17细胞的激活过程中也能够增强IL-21的产生。我们还表明，IL-6通过间接作用在CD4 T细胞上，诱导其IL-21产生，以及该IL-21作用于B细胞，从而增强了抗体反应。我们建议IL-6是有助于TFH细胞可塑性的主要先天免疫因子，从而通过调节CD4 T细胞中的IL-21表达而没有完全承诺，从而产生AB。我们还提出，由IL-6引起的可塑性是由其对两个独立信号通路的影响，1）STAT3，调节线粒体代谢和2）C/EBP2，提供了IL-21的选择性表达。 IL-6介导的可塑性可能是与CD4和B细胞反应的先天免疫反应整合的关键。我们将确定1）IL-6通过在NAIVE，效应子和记忆CD4 T细胞中进行调节诱导IL-21产生的IL-6对TFH细胞的可塑性的贡献（AIM 1），2）STAT3和C/EBP2转录因子的贡献通过促进记忆CD4 T细胞成为TFH细胞，IL-6介导的CD4 TFH细胞的可塑性（AIM 2），3）IL-6在保护性抗病毒记忆反应中的作用（AIM 3）。