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

描述（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信号诱导Th17细胞分化。典型（即由IL-6/TGF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，特别是在粘膜部位。为了表征G-l粘膜中这些Th17亚群的免疫保护性和免疫致病性特征，我们提出了4个特异性目的（SA）。在SA-1中，我们将描述和比较体外生成的Th17亚群在其过继转移到受体小鼠后的表型。同样，我们将在结肠炎模型中评估每个Th17亚群的炎症与调节功能。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细胞中携带特异性缺失刺激Ga蛋白（Gsa）的ko小鼠（GsaCD4 ko小鼠）。因此，在SA-2中，我们将评估GsaCD4和CD4 T细胞的细胞因子谱，它们对淋巴器官和G-l粘膜的归巢特性，以及它们在肠道炎症模型中的结肠炎谱。在SA-3中，我们将评估GsaCD4和CD4 T细胞是否介导宿主对微生物病原体的保护，即C. rodentium和H. pylori。我们将探讨非典型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的转化应用是设计基于camp的药物干预，靶向调节粘膜部位的CD4 T细胞功能。因此，在SA- 4中，我们将确定上述动物模型中camp升高药物的施用是否调节粘膜防御。我们提出的研究结果可以促进未来设计和开发旨在保护不同粘膜表面免受感染和免疫介导病理影响的疫苗和免疫疗法，这是本RFA的最终目标。

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.