ANALYSIS OF BACTERIAL-SPECIFIC COLONIC ITREG CELLS IN IMMUNE-MEDIATED COLITIS

描述(申请人提供)：免疫介导的结肠疾病，如炎症性肠病，可能与丧失对共生菌的耐受性有关。我们发现，在正常情况下，结肠耐受似乎是通过诱导调节性T(ITreg)细胞识别共生细菌来维持的。基于对结肠TCR谱系的研究，我们获得了两个表达细菌特异性iTreg TCR的新型转基因株系。这将使我们能够直接评估细菌特定的iTreg与 效应T细胞在不同实验条件下的分化。在目标1中，我们将操纵 使用TCR转基因株检测细菌群，并利用TCR谱系分析来确定它们对iTreg细胞生成的影响，以及对多克隆的CD4+T细胞群的影响。在目标2中，我们将研究T细胞识别细菌和分化为iTreg细胞而不是效应细胞所涉及的抗原提呈细胞和信号。最后，在目标3中，我们将超越正常生理学，研究感染以及与IBD相关的基因突变对iTreg细胞发育的影响，解决免疫介导性结肠炎期间CD4+T细胞耐受性被打破的假设。我们相信，了解调节细菌特异性结肠iTreg细胞发育和稳定性的机制将有助于促进Treg细胞介导的IBD治疗的发展。

DESCRIPTION (provided by applicant): Immune-mediated diseases of the colon such as inflammatory bowel disease may be related to a loss of tolerance to commensal bacteria. We have found that in the normal setting, colonic tolerance appears to be maintained via the recognition of commensal bacteria by inducible regulatory T (iTreg) cells. Based on our studies of the colonic TCR repertoire, we have generated two novel transgenic lines expressing bacteria- specific iTreg TCRs. This will allow us to directly assess bacteria-specific iTreg versus effector T cell differentiation under various experimental conditions. In Aim 1, we will manipulate the bacterial population and determine their impact on iTreg cell generation using the TCR transgenic lines, as well as on a polyclonal CD4+ T cell population using TCR repertoire analysis. In Aim 2, we will investigate the antigen-presenting cells and signals that are involved in T cell recognition of bacteria and differentiation into iTreg, rather than effector, cells. Finaly, in Aim 3, we will move beyond normal physiology and study the effect of infections as well as genetic mutations associated with IBD on iTreg cell development, addressing the hypothesis that CD4+ T cell tolerance is broken during immune mediated colitis. We believe that understanding the mechanisms which regulate the development and stability of bacteria-specific colonic iTreg cells will be useful for facilitating the development of Treg cell-mediated therapy fr IBD.