Regulation of Mucosal Inflammation by Th17 Subsets

淋巴组织中的T辅助（Th）细胞根据其位置发育成各种Th亚群， 调节炎症和防御。在肠粘膜中，其优势表型是调节型， Treg）细胞。通过克服粘膜Treg细胞的耐受性影响，粘液佐剂是独特的工具 用于解剖免疫调节和炎症。我们的初步数据表明，霍乱毒素（CT） 和相关化合物通过cAMP依赖性和IL-6/TGF β-不依赖性诱导Th 7细胞分化 通路为了阐明腺苷酸环化酶毒素和其他管腔微生物 TLR产物（TLR配体）刺激和调节粘膜微环境以促进效应子Thi 7 响应，我们在目的1中提出定义口服CT如何增强Th 17促进树突状细胞 细胞（DC）和抑制Treg促进DC。我们将探讨cAMP和视黄酸在这些过程中的作用。 过程，并表征随后的Th细胞反应引起的不同MLN DC亚群。在 目的2，我们将表征CD 4 T细胞的表型、稳定性和谱系分化标志物， 体外和体内分化的CT诱导的Thi 7亚群，并评估炎症/调节 口服CT对Thi 7细胞介导的结肠炎结局的影响。目标3将探讨 CT激活的DC在粘膜Thi 7应答中产生的CGRPP。目标4将研究潜在的 TLR刺激对CT诱导的Thi 7分化的贡献作用。剖析CT的影响， 其他cAMP诱导化合物对粘膜DC成熟的影响将显著拓宽我们对 粘膜Th反应的产生。通过分析CT诱导的粘膜Th 7细胞的谱系稳定性， 细胞，其效应功能，谱系承诺，运输及其与其他Th细胞的相互作用，我们将 增加我们对粘膜部位炎症和免疫调节的理解。数据 这些研究中产生的结果可能有助于设计新的粘膜炎性疾病治疗方法， 疾病和新型粘膜佐剂。 相关性（见说明）： 粘多糖佐剂对于口服疫苗接种策略的成功至关重要，因为抗原暴露本身 不会引发保护性免疫这些研究旨在增加对这些机制的理解 通过这种佐剂促进保护性免疫，也将产生对自然免疫的新见解。 肠道维持正常免疫稳态的机制。

T helper (Th) cells in lymphoid tissues, depending on their location, develop into various Th subsets to regulate inflammation and defense. In the intestinal mucosa, fheir dominant phenotype is that of regulatory T (Treg) cells. Mucosal adjuvants, by overriding the tolerizing impact of mucosal Treg cells, are unique tools for dissecting immune regulation and inflammafion. Our preliminary data indicate that cholera toxin (CT) and related compounds induce Thi7 cell differentiation via a cAMP-dependent and IL-6/TGF(3-independent pathway. To elucidate the mechanism by which adenylyl cyclase toxins and other luminal microbial products (TLR ligands) stimulate and modulate the mucosal microenvironment to promote effector Thi7 responses, we propose in Aim 1 to define how oral CT administrafion enhances Th17-promoting dendritic cells (DC) and suppresses Treg-promoting DC. We will explore the role of cAMP and retinoic acid in these processes, and characterize the subsequent Th cell response provoked by different MLN DC subsets. In Aim 2, we will characterize the phenotype, stability and lineage differentiation markers of CD4 T cells from in vitro- and in vivo-differentiated CT-induced Thi7 subsets, and evaluate the infiammatory/regulatory impact of orally delivered CT on the outcome of Thi7 cell-mediated colitis. Aim 3 will explore the role of CGRPP produced by CT-activated DC in a mucosal Thi7 response. Aim 4 will investigate the potential contributing role of TLR stimulation to CT-induced Thi7 differentiation. Dissecting the impact of CT and other cAMP-inducing compounds on mucosal DC maturation will significantiy broaden our knowledge on the generation of mucosal Th responses. By dissecting the lineage stability of CT-induced mucosal Thi7 cells, their effector function, lineage commitment, trafficking and their interactions with other Th cells, we will increase our understanding of the regulation of inflammation and immunity at mucosal sites. The data generated in these studies may help to design new therapeutic approaches for mucosal inflammatory diseases and novel mucosal adjuvants. RELEVANCE (See instmctions): Mucosal adjuvants are critical for success of oral vaccination strategies, since antigen exposure alone does not elicit protective immunity. The studies are designed to increase the understanding of the mechanisms by which such adjuvants promote protective immunity, and will also generate new insights into the natural mechanisms by which the gut maintains normal immune homeostasis.