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

调节 γ/δ 谱系承诺和效应脂肪的细胞外信号

• 批准号: 8608278
• 负责人: Juan Carlos Zuniga-Pflucker
• 金额: $ 35.04万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608278
• 关键词: Address; Adopted; Affect; Antigens; Bacterial Infections; Biological Models; Cell Line; Cells; Collection; Cues; Cytokine Receptors; Cytokine Signaling; Cytolysis; Dependency; Development; E protein; ES01; Enhancers; Epithelial Cells; Event; Fatty acid glycerol esters; Gene Expression; Gene Targeting; Generations; Homing; Immune system; In Vitro; Inflammation; Instruction; Interferons; Interleukin-17; Interleukin-4; Joints; Ligands; Link; Molecular; Nature; Outcome; Play; Process; Production; Receptor Signaling; Recruitment Activity; Regulation; Regulator Genes; Relative (related person); Role; STAT3 gene; Signal Transduction; Site; Source; Specific qualifier value; Stromal Cells; T cell differentiation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TCF3 gene; Testing; Therapeutic; Thymus Gland; Tissues; Work; Wound Healing; base; cancer cell; chemokine receptor; cytokine; extracellular; genetic variant; granulocyte; in vitro Model; in vivo; in vivo Model; insight; member; mouse model; notch protein; novel; pathogen; progenitor; programs; protein function; research study; response; transcription factor

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.

属于yδ-谱系的T细胞已被证明在免疫系统中起着独特和关键的作用。 系统γ δ T细胞广泛分布于富含粘膜和上皮细胞的组织中，是一种免疫调节细胞。 IL-17的重要早期来源，响应于许多病原体，将粒细胞募集到 炎症然而，γ δ T细胞如何获得作为IL-17产生细胞的应答能力， 抗原暴露仍不清楚。此外，γ δ T细胞如何被指定并分配给IL-17或 干扰素-γ（IFN γ）效应物命运仍有待充分阐明。最近的证据支持T 细胞受体（TCR）信号影响γ δ T细胞在胸腺内采用的效应功能类型， 成为产生干扰素-γ（IFN γ）、IL-4或IL-17的细胞。考虑到Notch的重要性 在整个T细胞分化的信号，我们假设，最终的分化和效应 yδ T细胞的功能选择受Notch受体-配体相互作用的指导，这会影响细胞的功能。 IFN γ产生与IL-17产生细胞的比较。我们将利用体外模型系统， 先前已经建立了阐明TCR、Notch和细胞因子信号在决定免疫应答中的作用。 yδ T细胞的最终效应子功能，并通过以下方式深入了解这些选择的分子基础： 组装全球基因调控网络。我们的目标是：1）研究Notch受体在肿瘤细胞中的作用， 2）阐明细胞因子受体信号在γ δ T细胞效应分化中的作用; 效应子分化;以及，3）确定E蛋白以及Notch和细胞因子的作用 信号，在指定γ δ T细胞效应器功能。综上所述，我们的联合实验方法和 这些发现将为控制yδ T细胞发育的分子过程提供重要的见解， 这是不可能的，如果没有本组织所有成员提供的综合专门知识， 程序.