ROLE OF NF-KB IN T CELL INFLAMMATION

NF-KB 在 T 细胞炎症中的作用

• 批准号: 6493982
• 负责人: Patrick Michael Flood
• 金额: $ 13.82万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6493982
• 关键词: T cell receptor; T lymphocyte; antigen presentation; genetic strain; genetically modified animals; immunogenetics; inflammation; laboratory mouse; nuclear factor kappa beta; tissue /cell culture

The existence of type-1 and type-2 cells in the CD4+ and CD8+ T cell populations has been well documented. Little is known, however, about the nature of the cellular signaling pathways that lead to the generation and maintenance of these phenotypes T cells and T cell clones. NF-kappaB is a family of transcription factors that have been shown to be of major importance in the activation and differentiation of T lymphocytes. While virtually nothing is known about the role of NF- kappaB activity in CD8+ T cells, it appears that NF-kappaB is differentially activated and regulated in type 1 versus. type 2 CD4+ T cell clones. We hypothesize that the activation conditions which differentially regulate the transcription factor NF-kappaB contributes to the commitment of T cells to the Th1/Tc1 or Th2/Tc2 cell lineage, and that this differential regulation plays a pivotal role in determining and maintaining their subset commitment. These different activation conditions include stimulation by the T cell receptor, by CD28, and/or exposure to cytokine IL-4 and IL-12. The purpose of this proposal is to determine the different mechanisms by which NF-kappaB is regulated in Th1/Tc1 and Th2/Tc2 cell subsets, and the consequence of this differential regulation on the phenotype and functional activity of these cells. We plan to 1): assess the differential expression of NF- kappaB in the T cell receptor (TcR) mediated activation of type 1 and type 2 CD4+ and CD8+ T cells by assessing how activation through TcR affects the functional activity of the different subunits. of the NF- kappaB. Determine the synergistic effects of cytokines and co- stimulation on NF-kappaB activation by TcR in primary T cells and T cell clones by determining if primary T cells and T cell. 3) Determine how suppression of NF-kappaB activation alters the phenotype and functional activity of T cell by measuring the effect of transducing a trans- dominant IkappaB repressor of NF-kappaB activity into Th1/Tc1 and Th2/Tc2 cell clones; and 4) Determine the effect of suppressing NF- kappaB activation in dendritic cells on the ability of DC to present antigen to Th1/Tc1 and Th2/Tc2. The effect of suppression of NF-kappaB activation in dendritic cells on the activation, development, and effector function of Th1/Tc1 and Th2/Tc2 cells will be assessed. These results will help us better understand how T cell subsets function during inflammatory responses, and determine if Nf-kappaB can be used as a target for therapeutic intervention designed to control T cell inflammation.

在CD4+和CD8+T细胞群中存在类型1和类型2的细胞已经被很好地记录下来。然而，对于导致这些表型T细胞和T细胞克隆的产生和维持的细胞信号通路的性质，人们知之甚少。核因子-kappaB是一个转录因子家族，已被证明在T淋巴细胞的激活和分化中起重要作用。虽然几乎不知道核因子-kappaB活性在CD8+T细胞中的作用，但似乎核因子-kappaB在1型与非1型T细胞中具有不同的激活和调节作用。2型CD4+T细胞克隆。我们假设，差异调节转录因子NF-kappaB的激活条件有助于T细胞对Th1/Tc1或Th2/Tc2细胞谱系的承诺，并且这种差异调节在决定和维持其亚群承诺方面发挥关键作用。这些不同的激活条件包括T细胞受体的刺激，CD28的刺激，和/或细胞因子IL-4和IL-12的暴露。本研究的目的是确定核因子-kappaB在Th1/Tc1和Th2/Tc2细胞亚群中的不同调控机制，以及这种不同调控对这些细胞的表型和功能活性的影响。我们计划1)：通过评估T细胞受体(TCR)激活对不同亚基功能活性的影响，评估核因子-kappaB在T细胞受体(TCR)介导的1型和2型CD4+和CD8+T细胞活化中的差异表达。核因子-kappaB。通过测定原代T细胞和T细胞的数量，确定细胞因子和共刺激对原代T细胞和T细胞克隆中TCR激活的核因子-kappaB的协同作用。3)通过测量将核因子-kappaB活性的反式抑制因子IkappaB转导到Th1/Tc1和Th2/Tc2细胞克隆的效果，确定抑制核因子-kappaB的激活如何改变T细胞的表型和功能活性；以及4)确定抑制树突状细胞中的核因子-kappaB的激活对DC向Th1/Tc1和Th2/Tc2递呈抗原的能力的影响。抑制树突状细胞中核因子-kappaB的激活对Th1/Tc1和Th2/Tc2细胞的激活、发育和效应功能的影响将被评估。这些结果将有助于我们更好地了解T细胞亚群在炎症反应中的功能，并确定核因子-kappaB是否可以作为旨在控制T细胞炎症的治疗干预的靶点。