INTESTINAL REGULATION OF ThPOK EXPRESSION AND CD4 HELPER T CELL FUNCTION

描述（由申请方提供）：占体内大部分淋巴细胞和抗体的庞大肠道相关免疫系统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应答。虽然CD 4辅助性T细胞对于产生有效的免疫应答至关重要，但不受控制的CD 4辅助性T细胞可能对生物体构成威胁。CD 4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CD 8细胞毒性T细胞命运取决于Runt家族的转录因子Runx 3。 我们最近发现了一种肠道特异性和高度可塑性的过程，该过程在CD 4 T细胞迁移到肠上皮后驱动ThPOK的下调。成熟CD 4 T细胞ThPOK的丧失伴随着T细胞辅助功能的抑制，特别是Th 17表型，以及Runx 3和细胞毒性相关分子的上调。 这是最感兴趣的是defieve的因素，调节辅助T细胞的稳定性和功能的结果，这些转录因子的调制成熟的CD 4辅助T细胞。 我们假设，在从外周迁移到肠腔，活化的CD 4 T细胞暴露于几个环境因素，可能编排这个过程。本研究将使用新型转基因小鼠品系和无菌动物来研究包括TGF-β、视黄酸和大肠杆菌在内的尿源性因子在调节CD 4辅助性T细胞功能中的作用。 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Runx 3调节的上游机制，以鉴定参与辅助性T细胞功能的下游靶标。最后，将使用感染和炎症性肠病（IBD）模型研究辅助性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Runx 3表达的调节如何影响CD 4 T细胞引起或控制炎症的能力。虽然ThPOK的伴随损失和Runx 3的获得可能有益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。本文提出的研究将直接解决肠道环境诱导的CD 4 T细胞外周可塑性在IBD发病机制和肠道感染控制中的功能影响。该提案完全使用新颖的概念，剖析了将辅助性T细胞向肠中的细胞毒性T细胞转移的生理途径，以解决CD 4辅助性T细胞分化和功能背后的生物学。因此，从本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，为宿主-微生物相互作用和疫苗接种策略提供有价值的信息。

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-ß, 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.