The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity

AP-1家族转录因子网络在调节Th17细胞效应子身份中的作用

基本信息

批准号：
9902487
负责人：
Maria Ciofani
金额：
$ 30.1万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902487
关键词：
Adopted Adoption Anti-Inflammatory Agents Attenuated Autoimmune Diseases Autoimmune Process Autoimmunity Bacteria CD4 Positive T Lymphocytes Candida albicans Cell Differentiation process Cell physiology Cells Characteristics Competence Development Disease Effector Cell Electron Transport Complex III Elements Environment Epigenetic Process Equilibrium Event Exhibits Family Future Gatekeeping Gene Expression Profile Genes Genetic Transcription Genomics Helper-Inducer T-Lymphocyte Immune response Immunity In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interferon Type II Interleukin-17 Intestines Knowledge Light Maintenance Mediating Mediator of activation protein Modeling Modification Molecular Monitor Mucosal Immunity Mucous Membrane Multiple Sclerosis Mus Pathogenicity Pathology Phenotype Play Psoriatic Arthritis Regulation Regulatory T-Lymphocyte Reporter Repression Rheumatoid Arthritis Role Site Surface T cell differentiation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Intervention Transcription Factor AP-1 Transcriptional Regulation Work attenuation cytokine effector T cell flexibility fungus immune activation immune clearance immunomodulatory therapies immunoregulation inhibitor/antagonist insight mouse model novel programs public health relevance response trait transcription factor

项目摘要

DESCRIPTION (provided by applicant): The role of AP-1 family transcription factor networks in regulating Th17 cell effector identity PROJECT SUMMARY CD4 T cells can adopt one of two opposing fates: that of a helper T cell (Th) specialized in supporting the clearance of infections, or that of a regulatory T cell (Treg) that functions to attenuate immune responses. Among the diversity of Th subset differentiation options, IL-17A-producing inflammatory Th17 cells stand out as unique by virtue of their relatively high level of inherent plasticity. Indeed, this subset hat normally functions in mucosal immunity against bacteria and fungi can easily adopt features of other T helper subsets when environmental conditions change. While this feature can be advantageous during the clearance of an infection, it is less beneficial during inflammatory disease. Indeed, dysregulated Th17 cell function has been implicated in numerous autoimmune conditions, including Inflammatory Bowel Disease, Multiple Sclerosis, Rheumatoid Arthritis and Psoriasis. Moreover, Th17 cell plasticity exhibited in the context of inflammatory disease tends to take on Th1-like traits, such as expression of IFNγ or T-bet, that are also associated with increased pathology. The underlying mechanisms that permit this plasticity are largely unknown. In this regard, we have recently identified several AP-1 family transcription factors with opposing roles in promotion versus limitation of Th17 cell plasticity. CD4 T cells lacking JunB exhibit dysregulated cytokine and transcription factor expression signatures both during in vitro differentiation, and in mouse models of inflammatory disease. In particular, JunB appears to restrain inappropriate Treg and Th1 differentiation. Here, we aim to test the hypothesis that JunB represents a novel controller of Th17 cell effector and regulatory switches, serving as a gate-keeper of Th17 cell plasticity. To this end, in Aim 1 we will perform conditional deletion of JunB using CD4- and Il17a- Cre deleter strains in the context of a fate-mapping reporter mouse to dissect the requirement for JunB in maintaining Th17 cell stability in diverse inflammatory disease and infection conditions. In Aim 2, we plan to decipher the molecular mechanisms of JunB-regulated Th17 stability. In this regard, we will (i) validate the JunB targets that facilitat subset interconversion events; (ii) define novel genomic lineage restriction elements and their mode of regulation by AP-1 complexes; and (iii) define activating and repressing roles of JunB that support Th17 lineage stability. Such mechanistic insight is key to guiding future work aimed at exploiting the AP-1 balance in Th17 cells to divert damaging inflammatory responses into favorable regulatory responses.

描述（申请人证明）：AP-1家族转录因子网络在调节Th17细胞效应子身份项目摘要D4 T细胞中的作用可以采用两个相对命运之一：辅助T细胞（TH）专门支持该命运清除感染，或炎症的炎症反应的作用（TREG）的炎症，这是炎症的炎症。当环境条件发生变化时，真菌可以轻松地采用其他T助手子集的特征，而在清除感染期间，这是有利的，在炎症性疾病期间，它的益处较小。此外，关节炎和牛皮癣。 AP-1家庭转录因素与相反缺乏JUNB的Th17 CD4 T细胞在促进与炎症的促进和限制中的作用是细胞因子和trans骨离子的分化和炎症疾病的小鼠模型。我们将使用CD4和IL17A-CRE对JUNB进行JUNB的贡献，以在EAIM 2中的E炎症疾病和感染条件中的Junb中的Junb中的JunB贡献。在这方面，我们将（i）验证限制事件的限制元素及其通过AP-1复合物进行调节的模式；支持Th17谱系稳定性的JUNB的角色是指导未来工作的LLS的关键，以将有害的炎症反应转移到有利的监管响应中。