Th17 subsets: Differential roles in immune defense mechanisms at the G-I mucosa

Th17 亚群：G-I 粘膜免疫防御机制中的不同作用

基本信息

批准号：
8711238
负责人：
Eyal Raz
金额：
$ 30.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711238
关键词：
Adenylate Cyclase Adjuvant Adoptive Transfer Affect Animal Model Animals CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Cholera Toxin Colitis Cyclic AMP Data Defense Mechanisms Frequencies Future G Protein-Coupled Receptor Genes Genes Helicobacter pylori Homing Host Defense Immune Immunotherapy In Vitro Infection Inflammation Inflammatory Inflammatory disease of the intestine Interleukin-17 Interleukin-2 Interleukin-6 Intervention Laboratories Lamina Propria Lymphocyte Subset Lymphoid Mediating Mesentery Modeling Mucosal Immunity Mucositis Mucous Membrane Mus Organ Pathology Pharmaceutical Preparations Phenotype Physiological Property Proteins Regulation Research Role Signal Transduction Spleen Surface System T-Lymphocyte Testing Wild Type Mouse base cytokine design gene therapy in vivo insight lymph nodes microbial mucosal site novel pathogen receptor response transcription factor vaccine development

项目摘要

DESCRIPTION (provided by applicant): While studying the mucosal adjuvant, cholera toxin, we recently identified It Induces Th17 cell differentiation via cAMP signaling. Canonical (I.e., induced by IL-6/TGFb) and non-canonical (i.e., induced by cAMP) Th17 subsets display different cytokine homing receptors and are regulated by different combinations of transcription factors. We hypothesize that these two Th17 subsets perform different physiological tasks especially at mucosal sites. To characterize the immunoprotective vs. immunopathogenic profiles of these Th17 subsets in the G-l mucosa, we proposed 4 specific aims (SA). In SA-1 we will characterize and compare the phenotype of the in vitro generated Th17 subsets after their adoptive transfer to recipient mice. Similarly, we will assess the inflammatory vs. regulatory function of each Th17 subset in a model of colitis. To explore the physiological role of cAMP signaling in Th17 differentiation in vivo, we generated ko mice that carry a specific deletion of the stimulatory Ga protein (Gsa) in CD4 T cells (GsaCD4 ko mice). Thus, in SA-2 we will evaluate the cytokine profile of GsaCD4 ko CD4 T cells, their homing properties to lymphoid organs and G-l mucosa, and their colitogenic profile in models of intestinal inflammation. In SA-3 we will evaluate whether GsaCD4 ko CD4 T cells mediate host protection against microbial pathogens, i.e., C. rodentium and H. pylori. We will examine the function of non-canonical Th17 cells in host defense, mucosal protection and mucosal inflammation. An important translational application of these studies is the design of cAMP-based pharmacological interventions that target the regulation of CD4 T cell functions in mucosal sites. Thus, in SA- 4 we will determine whether the administration of cAMP-elevating drugs regulate mucosal defense in the animal models described above. The results from our proposed research can facilitate the future design and development of vaccines and immunotherapies aimed at the protection of different mucosal surfaces from infections and immune-mediated pathology, which are the ultimate objectives of this RFA.

描述（由申请人提供）：在研究粘膜佐剂霍乱毒素时，我们最近确定它通过cAMP信号传导诱导Th17细胞分化。规范（即，由IL-6/TGFB诱导）和非典型的（即由CAMP诱导）Th17亚群显示出不同的细胞因子归巢受体，并由转录因子的不同组合调节。我们假设这两个TH17子集执行不同的生理任务，尤其是在粘膜部位。为了表征G-L Mucosa中这些Th17子集的免疫保护与免疫发病谱，我们提出了4个特定目标（SA）。在SA-1中，我们将表征和比较其在收养到接受者小鼠后体外产生的Th17子集的表型。同样，我们将在结肠炎模型中评估每个Th17子集的炎症与调节功能。为了探索CAMP信号在体内Th17分化中的生理作用，我们产生了KO小鼠，该KO小鼠在CD4 T细胞（GSACD4 KO小鼠）中携带特定的刺激GA蛋白（GSA）的特异性缺失。因此，在SA-2中，我们将评估GSACD4 KO CD4 T细胞的细胞因子谱，其对淋巴机构和G-L Mucosa的归巢特性以及其在肠道炎症模型中的造成生成谱。在SA-3中，我们将评估GSACD4 KO CD4 T细胞是否介导了针对微生物病原体的宿主保护，即C. rodentium和H. Pylori。我们将检查非典型Th17细胞在宿主防御，粘膜保护和粘膜炎症中的功能。这些研究的一个重要翻译应用是基于营地的药理学干预措施的设计，该干预措施针对粘膜部位中CD4 T细胞功能的调节。因此，在SA-4中，我们将确定在上述动物模型中，cAMP升高药物的给药是否调节粘膜防御。我们提出的研究的结果可以促进旨在保护不同粘膜表面免受感染和免疫介导的病理学的疫苗和免疫疗法的未来设计和开发，这是该RFA的最终目标。