EFFECTOR VERSUS REGULATORY T SUBSET RESPONSE TO THE MICROBIOTA

炎症性肠病(IBD)是一种免疫失调疾病。来自许多IBD小鼠模型的证据和来自人类研究的新数据支持，作为一种常见的致病机制，失调的CD4T细胞对肠道菌群组分的反应是一种核心作用。传统上，与IBD相关的效应性T细胞反应被认为是在Th1/Th2范式的背景下进行的，其中对肠道细菌抗原的识别要么诱导典型的Th1细胞因子(干扰素-γ和肿瘤坏死因子-α)，要么诱导Th2细胞因子(IL-4、IL-13和IL-5)。在许多IBD的小鼠模型中，以及在克罗恩病中，流行的观点是，致病的是调节失调的Th1反应。然而，最近的研究指出，有必要 对现有的Th1范式进行批判性的重新评估。在传统上被视为Th1疾病模型的实验性自身免疫性脑脊髓炎(EAE)和胶原性关节炎中，发现效应性T细胞IL-17的产生与疾病的发病机制有关，挑战了经典Th1细胞在诱导中的重要性 以及慢性炎症性疾病的维持。这些效应细胞因子是由不同的IL-12家族成员相互诱导的，因此IL-12有利于产生IFN-γ的T细胞的发展，而IL-23有利于产生IL-17的T细胞。值得注意的是，在单个T细胞中，IFNGamma或IL-17的表达往往是相互排斥的。这些研究提出了重要的问题，即IL-17和IFN-γ产生的“Th1”细胞之间的谱系关系，以及这些细胞因子在疾病发病机制或保护中的各自作用。我们假设，现有的IBD和克罗恩病的Th1模型实际上是由于肠道菌群对IL-17的反应失调所致，并且产生IFN-γ的T细胞是非致病效应细胞，在适当的条件下可以从中产生产生IL-17的致病效应细胞。为了验证我们的假设，我们已经生成了一个新的IFNGamma报告基因转基因模型，并将生成一个补充的IL-17报告模型，以在抗原特异性的IBD小鼠模型的背景下检查这些T细胞表型的诱导、谱系关系和调节。此外，我们将利用IL-10探索调节性T细胞与这些不同的效应T细胞群之间的相互作用 我们为独立研究肠道调节性T细胞生物学而开发的报告模型。最终，这些研究将形成与从正常和疾病的人类肠道组织中分离出来的T效应细胞和T调节细胞的比较研究的基础，这些组织对此知之甚少。我们的具体目标是检验上述假设的三个不同但相关的方面：1.IL-23/IL-17细胞因子轴是IBD免疫发病所必需的：2.IL-17- 产生CD4T细胞代表了Th1效应细胞的不同群体，这些细胞是从组织效应部位产生干扰素-γ的中间产物发展而来的，例如肠道固有层：和。3.产生IL-10的调节性T细胞抑制肠道固有层产生IL-17的效应T细胞的发育和维持。

Inflammatory bowel diseases (IBD) are diseases of immune dysregulation. Evidence from a number of mouse models of IBD, and emerging data from human studies, support a central role for dysregulated CD4 T cell responses to components of the enteric flora as a common pathogenetic mechanism. Effector T cell responses linked to IBD have traditionally been viewed in the context of the Th1/Th2 paradigm, wherein recognition of enteric bacterial antigens elicit either prototypical Th1 cytokines (IFN-gamma and TNF-alpha) or Th2 cytokines {IL-4, IL-13, and IL-5). In many mouse models of IBD, and in Crohn's disease, the prevailing view is that it is a dysregulated Th1 response that is pathogenic. However, recent studies point to a need for critical reassessment of the existing Th1 paradigm. In experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis, both conventionally viewed as Th1 disease models, it was found that effector T cell production of IL-17, and not IFNgamma, was linked to disease pathogenesis, challenging the significance of classical Th1 cells in the induction and maintenance of chronic inflammatory disease. These effector cytokines were reciprocally induced by distinct IL-12 family members, such that IL-12 favored development of IFNgamma-producing T cells, whereas IL-23 favored IL-17 producers. Notably, expression of IFNgamma or IL-17 tended to be mutually exclusive in individual T cells. These studies have raised important questions regarding the lineage relationships between IL-17- versus IFNgamma-producing "Th1" cells, and the respective roles of these cytokines in disease pathogenesis or protection. We hypothesize that existing Th1 models of IBD, and Crohn's disease, are in fact due to dysregulated IL-17 responses to the intestinal flora, and that IFNgamma-producing T cells are non-pathogenic effectors from which IL-17-producing, pathogenic effectors can develop under the appropriate conditions. To test our hypothesis, we have generated a novel IFNgamma reporter transgenic model and will generate a complementary IL-17 reporter model to examine the induction, lineage relationships and regulation of these T cell phenotypes in the context of an antigen-specific mouse model of IBD. Further, we will explore the interplay of regulatory T cells with these distinct effector T cell populations, utilizing an IL-10 reporter model that we have developed for independent studies of intestinal regulatory T cell biology. Ultimately, these studies will form the basis for comparative studies with T effector and T regulatory cells isolated from normal and diseased human intestinal tissues, about which little is known. Our specific aims are to test three distinct, but related, aspects of the above hypothesis: 1. The IL-23/IL-17 cytokine axis is required for immunopathogenesis in IBD: 2. IL-17- producing CD4 T cells represent a distinct population of Th1 effector cells that develop from IFNgamma-producing intermediates at tissue effector sites, such as the intestinal lamina propria: and. 3. IL-10-producing regulatory T cells suppress the development and maintenance of IL-17-producing effector T cells in the intestinal lamina propria.