Novel Mucosal Regulatory DC4+ T Cells: Interface Between Th17 and Treg

本项目中拟议的研究基础反映了最初和第二次世界大战期间的调查结果， 在我们实验室的长期观察中，调节性T细胞在与正常细胞相互作用后被激活， 肠上皮细胞这些研究还记录了当上皮细胞增殖时，CD 8 + Treg活化的缺陷。 来源于IBD患者的细胞用于活化T细胞。在确定《公约》的所有剧目的过程中， 调节性T细胞存在于正常和发炎的肠道在最后一个授予周期，我们确定了一个 CD固有层中的新的CD 4 + FoxP 3/IL 17双阳性细胞群，但UC或正常人中没有 患者这些细胞具有分泌IL 17、IL 22的Th 17细胞的表型特征。IL21， 表达高水平的CCR 6、CD 161和ROR γ t。然而，与常规的Th 17（细胞和类似的Th 17）不同， FoxP 3 + TcR，它们表达高水平的CD 101和低水平的CD 127，表现出类似的TcR库 (BV使用），并且在体外共培养系统中具有功能抑制性。FoxP 3 +IL-17产生细胞是 印记为肠道归巢，如通过高水平的CCR 6、CD 103和整合素α 4 β 7表达所指示的。 这些细胞分泌IFN γ，但不分泌IL 10或TGFB。因此，它们代表了一种新的细胞群， 提供了有用的见解Tcl 4细胞与Th 17细胞的谱系定型。我们建议这些细胞位于 在Treg和Th 17细胞之间的十字路口，并且进一步致力于任何一个谱系的结果， 组织中存在的微环境线索。目前的建议旨在描述这些细胞的特征， 定义参与其激活的因素。最重要的是，我们的目标是确定微环境线索， 这使得这些细胞定型为Th 17（更可能在CD中）而不是调节谱系。我们将：1） 定义来源于以下的CD 4 + FoxP 3/IL 17双阳性细胞的功能和表型特性： CD; 2）定义导致调节谱系的转录程序的微环境线索 这些细胞的承诺。在项目3（IRF 8）中与熊博士合作，评估相互作用 在FoxP 3和RORyt之间，并确定允许两种转录的负调控的因子 因素3)在小鼠回肠炎/结肠炎模型或小鼠感染模型中鉴定这些细胞的对应物， 与里拉博士和Blander博士合作，以确定其体内生成所需的条件。

The basis of the studies proposed in this project reflect the findings emanating from the initial and longstanding observations in our lab that regulatory T cells are activated following interactions with normal intestinal epithelial cells. These studies also documented defects in CD8+ Treg activation when epithelia cells derived from IBD patients were used to activate T cells. During the course of defining the repertoire of regulatory T cells present in normal and inflamed intestine during the last granting cycle, we identified a novel population of CD4+ FoxP3/IL17 double positive cells in the lamina propria of CD but not UC or normal patients. These cells share phenotypic characteristics of Th17 cells with secretion of IL17, IL22. IL21 while expressing high levels of CCR6, CD161, and RORyt. However, unlike conventional Th17 (cells and similar to FoxP3+ Tregs, they express high levels of CD101 and low levels of CD127, exhibit a similar TcR repertoire (BV usage) and are functionally suppressive in in vitro co-culture systems. FoxP3+IL-17 producing cells are imprinted for gut homing, as indicated by high levels of CCR6, CD103 and the integrin a4B7 expression. These cells secrete IFNy but not IL10 or TGFB. Thus they represent a novel cell population that could provide useful insights into lineage commitment of Tregs versus Th17 cells. We propose that these cells sit at the crossroads between Treg and Th17 cells and that further commitment to either lineage results from microenvironmental cues present in the tissues. The current proposal seeks to characterize these cells and define factors involved in their activation. Most importantly we aim to detemiine the microenvironmental cues that allow these cell to commit to a Th17 (more likely in CD) rather than a regulatory lineage. We will: 1) Define the functional and phenotypic properties of the CD4+ FoxP3/IL17 double positive cells derived from CD; 2) Define the microenvironmental cues leading to a transcriptional program that regulates lineage commitment of these cells. In collaboration with Dr. Xiong in Project 3 (IRF8), assess the interactions between FoxP3 and RORyt and determine factors that allow for negative regulation of both transcription factors. 3) Identify counterparts of these cells in murine models of ileitis/colitis or murine infection models in collaboration with Drs. Lira and Blander to establish the conditions required for their generation in vivo.