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：
8180220
负责人：
Eyal Raz
金额：
$ 32.83万
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/8180220
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 Principal Investigator Property Proteins Regulation Research Role Signal Transduction Spleen Surface System T-Lymphocyte Testing Wild Type Mouse base cytokine design 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/TGF¿) 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. PUBLIC HEALTH RELEVANCE: In this application we will investigate two subsets of lymphocytes in models of intestinal inflammation and infection. Using appropriate mice that we generated, we will determine which of this subset is protective and which is inflammatory in the gut. Using appropriate drugs, we will attempt to modulate the inflammatory cell to function in a protective mode.

描述：研究粘膜佐剂，霍乱托米因营地信号传导（即由IL-6/TGF诱导）和非官方（即由CAMP诱导）TH17喷雾不同的细胞因子归宿Theset的转录因子在G-L粘膜中的TH17子集的粘膜位点上进行了不同的生理学转移到接受者小鼠。 CD4 T细胞中的蛋白质（GSA）（GSACD4 KO小鼠）。 T细胞介导宿主保护，即鼠尾草和幽门螺杆菌。 CD4的基于营地的药物介入目标targe的目标是cAMP的造型。表面感染和免疫介导的病理学，这是该RFA的最终目标。公共卫生相关性：在本应用程序中，我们将在我们产生的炎症和感染模型中调查两个淋巴细胞的子集。在保护模式下发挥作用的炎症细胞。