Extracellular cues that regulate gamma/delta lineage commitment and effector fat

属于yδ血统的T细胞已被证明在免疫中起着独特和关键的作用。 系统。YδT细胞广泛分布于粘膜和富含上皮细胞的组织中，是一种 IL-17的重要早期来源对多种病原体的反应，将粒细胞募集到 发炎。然而，yδT细胞是如何获得作为产生IL-17的细胞在 抗原暴露情况仍不清楚。此外，yδT细胞如何被指定和分配给IL-17或 干扰素-γ(IFNy)效应的命运仍未完全阐明。最近的证据支持这样一个观点，即T 细胞受体(TCR)信号影响YδT细胞在胸腺内采用的效应器功能类型，如 作为干扰素-γ(IFNy)、IL-4或IL-17的产生细胞。鉴于Notch的关键重要性 在T细胞分化的整个信号传递过程中，我们假设最终的分化和效应 Y-δT细胞的功能选择是由Notch受体-配体相互作用引导的，这种相互作用影响 产生干扰素和产生IL-17的细胞。我们将利用我们的体外模型系统 先前已建立以阐明TCR、Notch和细胞因子信号在决定 YδT细胞的最终效应功能，并通过以下方式深入了解这些选择的分子基础 组建全球基因调控网络。我们的目标是：1)解决Notch受体的作用 信号在yδT细胞效应器分化中的作用；2)探讨细胞因子受体信号在yδT细胞中的作用 以及，3)确定E蛋白与Notch和细胞因子的作用 信号，在指定yδT细胞效应器功能时。综上所述，我们的联合实验方法和 这些发现将为控制yδT细胞发育和 如果没有本组织所有成员提供的综合专业知识，这是不可能的 程序。

T cells belonging to the yδ-lineage have been shown to serve a unique and critical role within the immune system. yδ T cells are widely distributed throughout mucosal and epithelial cell-rich tissues and are an important early source of IL-17 in response to a number of pathogens, recruiting granulocytes to the site of inflammation. However, how yδ T cells acquire the ability to respond as IL-17-producing cells prior to antigen exposure remains unclear. Additionally, how yδ T cells become specified and assigned to IL-17 or interferon-y (IFNy) effector fates remains to be fully elucidated. Recent evidence supports the notion that T cell receptor (TCR) signals affect the type of effector function that yδ T cells adopt within the thymus, such as becoming interferon-y (IFNy), IL-4 or IL-17 producing cells. Given the critical importance of Notch signaling throughout T cell differentiation, we hypothesized that the final differentiation and effector function selection by yδ T cells is guided by Notch receptor-ligand interactions, which influence the generation of IFNy vs. IL-17 producing cells. We will take advantage of the in vitro model system that we have previously established to elucidate the roles for TCR, Notch and cytokine signals in determining the final effector function of yδ T cells, and gain insight into the molecular basis for these selections by assembling global gene regulatory networks. Our aims are: 1) to address the role of Notch receptor signaling in yδ T cell effector differentiation; 2) to address the role of cytokine receptor signaling in yδ T cell effector differentiation; and, 3) to determine the role of E-proteins, together with Notch and cytokine signals, in specifying yδ T cell effector function. Taken together, our joint experimental approach and findings will provide important insights into the molecular processes controlling yδ T cell development and function, which would not be possible without the combined expertise provided by all members of this program.