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

描述（由申请人提供）：在研究粘膜佐剂霍乱毒素时，我们最近鉴定了它通过cAMP信号传导诱导Th 17细胞分化。Canonical（即，由IL-6/TGF β诱导）和非典型（即，由cAMP诱导）Th 17亚群显示不同的细胞因子归巢受体，并受不同转录因子组合的调节。我们假设这两个Th 17亚群执行不同的生理任务，特别是在粘膜部位。为了表征这些Th 17亚群在G-I粘膜中的免疫保护性对免疫病理性概况，我们提出了4个具体目标（SA）。在SA-1中，我们将表征和比较体外产生的Th 17亚群过继转移至受体小鼠后的表型。类似地，我们将评估结肠炎模型中每个Th 17亚群的炎症与调节功能。为了探索cAMP信号传导在体内Th 17分化中的生理作用，我们产生了在CD 4 T细胞中携带刺激性Ga蛋白（Gsa）的特异性缺失的ko小鼠（GsaCD 4 ko小鼠）。因此，在SA-2中，我们将评估GsaCD 4 ko CD 4 T细胞的细胞因子谱、它们对淋巴器官和G-I粘膜的归巢特性以及它们在肠道炎症模型中的大肠杆菌谱。在SA-3中，我们将评估GsaCD 4 ko CD 4 T细胞是否介导宿主对微生物病原体的保护，即，C. rodentium和H.幽门。我们将研究非典型Th 17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以调节粘膜部位CD 4 T细胞功能为目标的基于cAMP的药理学干预。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疫苗和免疫疗法的未来设计和开发，旨在保护不同的粘膜表面免受感染和免疫介导的病理，这是RFA的最终目标。 公共卫生相关性：在本申请中，我们将研究肠道炎症和感染模型中的两个淋巴细胞亚群。使用我们产生的适当小鼠，我们将确定哪个亚组是保护性的，哪个是肠道炎症性的。使用适当的药物，我们将尝试调节炎症细胞以保护模式发挥作用。

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.