INTESTINAL REGULATION OF ThPOK EXPRESSION AND CD4 HELPER T CELL FUNCTION

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扩散，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辅助性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辅助性T细胞可能对生物体构成威胁。CD4命运最初在胸腺细胞中诱导，并在成熟T细胞中由锌指转录因子ThPOK持续维持，而CD8细胞毒性T细胞命运则依赖于Runt家族的转录因子Runx3。我们最近发现了一个肠道特异性和高度可塑性的过程，该过程驱动CD4 T细胞迁移到肠上皮时ThPOK的下调。成熟CD4 T细胞的ThPOK缺失伴随着T细胞辅助功能（尤其是Th17表型）的抑制，以及Runx3和细胞毒性相关分子的上调。在成熟的CD4辅助性T细胞中，定义调节辅助性T细胞稳定性的因子和这些转录因子的调节的功能后果是最感兴趣的。我们假设在从外周到肠隔室的迁移过程中，活化的CD4 T细胞暴露于几种可能协调这一过程的环境因素中。本研究将采用新型转基因小鼠品系和无菌动物，探讨TGF-ß、视黄酸和共生菌等肠源性因子在调节CD4辅助性T功能中的作用。此外，生物信息学与表观遗传学相关

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.