INTESTINAL REGULATION OF ThPOK EXPRESSION AND CD4 HELPER T CELL FUNCTION

ThPOK 表达和 CD4 辅助 T 细胞功能的肠道调节

• 批准号: 8594245
• 负责人: Daniel S Mucida
• 金额: $ 36.87万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8594245
• 关键词: Accounting; Address; Animals; Antibiotics; Antibodies; Antigens; Area; Bioinformatics; Biology; CD4 Positive T Lymphocytes; CD8B1 gene; Celiac Disease; Cell physiology; ChIP-on-chip; Colitis; Complex; Cytotoxic T-Lymphocytes; Development; Diet; Dominant-Negative Mutation; Down-Regulation; Environmental Risk Factor; Epigenetic Process; Epithelial; Family; Food Hypersensitivity; Generations; Genes; Germ-Free; Helper-Inducer T-Lymphocyte; Human Development; Immune; Immune response; Immune system; Indigenous; Infection; Inflammation; Inflammatory Bowel Diseases; Intestines; Knowledge; Lead; Lymphocyte; Mature T-Lymphocyte; Microbe; Modeling; Molecular; Monitor; Mouse Strains; Mus; Organism; Pathogenesis; Pathway interactions; Penetration; Peripheral; Phenotype; Physiological; Plastics; Process; Public Health; Regulatory T-Lymphocyte; Reporter; Research; Role; System; T-Cell Development; T-Lymphocyte; Techniques; Tissues; Transcriptional Regulation; Tretinoin; Up-Regulation; Zinc Fingers; adaptive immunity; commensal microbes; cytokine; cytotoxic; in vivo; interest; intestinal epithelium; loss of function; microorganism interaction; migration; mucosal vaccine; novel; novel strategies; novel therapeutics; overexpression; pathogen; public health relevance; research study; thymocyte; transcription factor; vaccination strategy

DESCRIPTION (provided by applicant): The vast gut-associated immune system, which accounts for most of the lymphocytes and antibodies in the body, must inhibit penetration and spreading of pathogens while controlling excessive or unnecessary immune responses that could jeopardize the integrity of the mucosal epithelial barrier. Although CD4 helper T cells are crucial for the generation of efficient immune responses, uncontrolled CD4 helper T cells can pose a threat to an organism. The CD4 fate is initially induced in thymocytes and continuously maintained in mature T cells by the zinc finger transcription factor, ThPOK, while CD8 cytotoxic T cell fate depends on the transcription factor of Runt family, Runx3. We recently found a gut specific and highly plastic process that drives the downregulation of ThPOK in CD4 T cells upon migration to the intestinal epithelium. The loss of ThPOK by mature CD4 T cells is accompanied by suppression of T cell helper function, particularly the Th17 phenotype, and upregulation of Runx3 and cytotoxic-related molecules. It is of utmost interest to defie factors that regulate the stability of helper T cells and functional consequences of modulation of these transcription factors in mature CD4 helper T cells. We hypothesize that during migration from the periphery to the intestinal compartment, activated CD4 T cells are exposed to several environmental factors that may orchestrate this process. This study will use novel genetically modified mouse strains and germ-free animals to investigate the role of intestinal-derived factors including TGF-?, retinoic acid and commensal bacteria, in the modulation of CD4 helper T function. Additionally, bioinformatics associated with epigenetics techniques will be used to define upstream mechanisms that drive ThPOK and Runx3 modulation as to identify downstream targets involved in helper T cell function. Finally, the functional consequences of this unpredicted plasticity of helper T cells will be studied using models of infection and inflammatory bowel diseases (IBD). In vivo experiments will determine how the modulation of ThPOK and Runx3 expression in the intestine influences the capacity of CD4 T cells to cause or control inflammation. While the concomitant loss of ThPOK and acquisition of Runx3 may be beneficial to avoid excessive inflammation and tissue destruction, it may be detrimental when specific. The cytokines are required for immune protection. The studies proposed here will directly address functional implications of the peripheral plasticity of CD4 T cells, induced by intestinal milieu, in the IBD pathogenesis and in the control of intestinal infections. This proposal uses exclusively novel concepts, dissecting a physiological pathway that shifts helper T cells towards cytotoxic T cells in the intestine, to address the biology behin CD4 T cells helper differentiation and function. Therefore, by the knowledge gained from this study will expand our understanding of the development and modulation of the adaptive immunity, providing valuable information regarding host-microbial interactions and vaccination strategies.

描述（由申请人提供）：庞大的肠道相关免疫系统占体内大部分淋巴细胞和抗体，必须抑制病原体的渗透和传播，同时控制可能危及粘膜上皮屏障完整性的过度或不必要的免疫反应。尽管 CD4 辅助 T 细胞对于产生有效的免疫反应至关重要，但不受控制的 CD4 辅助 T 细胞可能对生物体构成威胁。 CD4 的命运最初在胸腺细胞中诱导，并通过锌指转录因子 ThPOK 在成熟 T 细胞中持续维持，而 CD8 细胞毒性 T 细胞的命运则取决于 Runt 家族的转录因子 Runx3。 我们最近发现了一种肠道特异性且高度可塑的过程，该过程在迁移到肠上皮时驱动 CD4 T 细胞中 ThPOK 的下调。成熟 CD4 T 细胞丧失 ThPOK 伴随着 T 细胞辅助功能（特别是 Th17 表型）的抑制，以及 Runx3 和细胞毒性相关分子的上调。 人们最感兴趣的是对抗调节辅助 T 细胞稳定性的因子以及在成熟 CD4 辅助 T 细胞中调节这些转录因子的功能后果。 我们假设，在从外周迁移到肠室的过程中，活化的 CD4 T 细胞暴露于可能协调这一过程的多种环境因素。本研究将使用新型转基因小鼠品系和无菌动物来研究肠道衍生因子（包括 TGF-β、视黄酸和共生细菌）在调节 CD4 辅助 T 功能中的作用。 此外，与表观遗传学相关的生物信息学 技术将用于定义驱动 ThPOK 和 Runx3 调制的上游机制，以确定参与辅助 T 细胞功能的下游靶标。最后， 将使用感染和炎症性肠病 (IBD) 模型来研究辅助 T 细胞这种不可预测的可塑性的功能后果。体内实验将确定肠道中 ThPOK 和 Runx3 表达的调节如何影响 CD4 T 细胞引起或控制炎症的能力。虽然 ThPOK 的同时丢失和 Runx3 的获得可能有利于避免过度炎症和组织破坏，但在特定情况下可能是有害的。细胞因子是免疫保护所必需的。这里提出的研究将直接解决外围可塑性的功能影响 由肠道环境诱导的 CD4 T 细胞在 IBD 发病机制和肠道控制中的作用 感染。该提案采用了独特的新颖概念，剖析了肠道中辅助 T 细胞向细胞毒性 T 细胞转变的生理途径，以解决 CD4 T 细胞辅助分化和功能背后的生物学问题。因此，从这项研究中获得的知识将扩大我们对适应性免疫的发展和调节的理解，提供有关宿主-微生物相互作用和疫苗接种策略的有价值的信息。