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，我们最近发现它通过 cAMP 信号传导诱导 Th17 细胞分化。典型（即由 IL-6/TGFb 诱导）和非典型（即由 cAMP 诱导）Th17 亚群表现出不同的细胞因子归巢受体，并受到不同转录因子组合的调节。我们假设这两个 Th17 亚群执行不同的生理任务，尤其是在粘膜部位。为了表征 G-1 粘膜中这些 Th17 亚群的免疫保护性与免疫致病性特征，我们提出了 4 个具体目标 (SA)。在 SA-1 中，我们将表征并比较体外生成的 Th17 亚群在过继转移至受体小鼠后的表型。同样，我们将评估结肠炎模型中每个 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，我们培育了 CD4 T 细胞中刺激性 Ga 蛋白 (Gsa) 特异性缺失的 ko 小鼠（GsaCD4 ko 小鼠）。因此，在SA-2中，我们将评估GsaCD4 ko CD4 T细胞的细胞因子谱、它们对淋巴器官和G-1粘膜的归巢特性以及它们在肠道炎症模型中的致结肠炎谱。在 SA-3 中，我们将评估 GsaCD4 ko CD4 T 细胞是否介导宿主针对微生物病原体（即啮齿类弯曲杆菌和幽门螺杆菌）的保护。我们将研究非典型 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转化应用是设计基于 cAMP 的药理学干预措施，其目标是调节粘膜部位的 CD4 T 细胞功能。因此，在SA-4中，我们将确定cAMP升高药物的施用是否调节上述动物模型中的粘膜防御。我们提出的研究结果可以促进未来疫苗和免疫疗法的设计和开发，旨在保护不同粘膜表面免受感染和免疫介导的病理学影响，这是本次 RFA 的最终目标。