Regulation of Mucosal Inflammation by Th17 Subsets

Th17 亚群对粘膜炎症的调节

• 批准号: 7757163
• 负责人: Eyal Raz
• 金额: $ 22.82万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7757163
• 关键词: Adenylate Cyclase; Adjuvant; Antigens; Biological Assay; CD4 Positive T Lymphocytes; Calcitonin Gene-Related Peptide; Cell Differentiation process; Cell Maturation; Cells; Cholera Toxin; Colitis; Cyclic AMP; Data; Dendritic Cells; Differentiation Antigens; Disease; Environment; GTP-Binding Proteins; Generations; Genes; Helper-Inducer T-Lymphocyte; Homeostasis; Homing; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; Inflammatory; Integrins; Interleukin-17; Intestinal Mucosa; Intestines; Knock-out; Knockout Mice; Knowledge; Lamina Propria; Ligands; Location; Lymphoid Tissue; Mediating; Molecular Profiling; Mucositis; Mus; Neuropeptides; Oral; Oral Administration; Outcome; Pathway interactions; Peptides; Phenotype; Physiological; Play; Process; Regulation; Research Design; Role; Signal Transduction; T-Lymphocyte; Toxin; Tretinoin; Wild Type Mouse; cytokine; design; in vivo; insight; microbial; mucosal site; novel; novel therapeutic intervention; receptor; receptor-activity-modifying protein; response; success; tool; trafficking; vaccination strategy; Adenylate Cyclase; Adjuvant; Antigens; Biological Assay; CD4 Positive T Lymphocytes; Calcitonin Gene-Related Peptide; Cell Differentiation process; Cell Maturation; Cells; Cholera Toxin; Colitis; Cyclic AMP; Data; Dendritic Cells; Differentiation Antigens; Disease; Environment; GTP-Binding Proteins; Generations; Genes; Helper-Inducer T-Lymphocyte; Homeostasis; Homing; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammation; Inflammatory; Integrins; Interleukin-17; Intestinal Mucosa; Intestines; Knock-out; Knockout Mice; Knowledge; Lamina Propria; Ligands; Location; Lymphoid Tissue; Mediating; Molecular Profiling; Mucositis; Mus; Neuropeptides; Oral; Oral Administration; Outcome; Pathway interactions; Peptides; Phenotype; Physiological; Play; Process; Regulation; Research Design; Role; Signal Transduction; T-Lymphocyte; Toxin; Tretinoin; Wild Type Mouse; cytokine; design; in vivo; insight; microbial; mucosal site; novel; novel therapeutic intervention; receptor; receptor-activity-modifying protein; response; success; tool; trafficking; vaccination strategy

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.

淋巴组织中的T助手（Th）细胞，取决于其位置，发展成各种子集 调节炎症和防御。在肠粘膜中，FHEIR显性表型是调节的 T（Treg）细胞。粘膜佐剂通过覆盖粘膜Treg细胞的耐受影响是独特的工具 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） 相关化合物通过CAMP依赖性和IL-6/TGF诱导Thi7细胞分化（3个独立 路径。阐明腺苷酸环化酶毒素和其他腔微生物的机制 产品（TLR配体）刺激并调节粘膜微环境以促进效应子Thi7 回答，我们在AIM 1中提出了旨在定义口服CT Idministrafion如何增强TH17促进树突状的 细胞（DC）并抑制促进Treg的DC。我们将探索营地和视黄酸在这些中的作用 过程，并表征随后由不同的MLN DC子集引起的细胞响应。在 AIM 2，我们将表征CD4 T细胞的表型，稳定性和谱系分化标记 体外和体内分化的CT诱导的Thi7子集，并评估侵害性/调节性 口服递送CT对Thi7细胞介导的结肠炎结果的影响。 AIM 3将探讨 CT激活的DC在粘膜Thi7响应中产生的CGRPP。 AIM 4将调查潜力 TLR刺激对CT诱导的Thi7分化的作用。剖析CT的影响 其他关于粘膜DC成熟的营地诱导化合物将大大扩大我们对 粘膜的产生。通过剖析CT诱导的粘膜Thi7的谱系稳定性 细胞，效应子功能，谱系承诺，运输及其与其他TH细胞的相互作用，我们将 提高我们对粘膜部位炎症和免疫力的调节的理解。数据 在这些研究中产生的可能有助于设计新的治疗方法来粘膜炎症 疾病和新型粘膜佐剂。 相关性（请参阅Instmctions）： 粘膜佐剂对于口服疫苗接种策略的成功至关重要，因为仅抗原暴露才能 不引起保护性免疫。研究旨在增加对机制的理解 通过这种佐剂促进保护性免疫，还将产生对自然的新见解 肠道维持正常免疫稳态的机制。