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.

CD4+ 和 CD8+ T 细胞群中 1 型和 2 型细胞的存在已得到充分记录。然而，人们对导致这些表型 T 细胞和 T 细胞克隆的产生和维持的细胞信号传导途径的性质知之甚少。 NF-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具有重要作用。虽然实际上对 NF-kappaB 活性在 CD8+ T 细胞中的作用一无所知，但 NF-kappaB 在 1 型和 1 型 T 细胞中的激活和调节似乎存在差异。 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 细胞向 Th1/Tc1 或 Th2/Tc2 细胞谱系的定型，并且这种差异调节在确定和维持其子集定型方面发挥着关键作用。这些不同的激活条件包括 T 细胞受体、CD28 的刺激和/或暴露于细胞因子 IL-4 和 IL-12。本提案的目的是确定 NF-kappaB 在 Th1/Tc1 和 Th2/Tc2 细胞亚群中调节的不同机制，以及这种差异调节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 TcR 激活如何影响不同亚基的功能活性，评估 NF-kappaB 在 T 细胞受体 (TcR) 介导的 1 型和 2 型 CD4+ 和 CD8+ T 细胞激活中的差异表达。 NF-κB。通过确定原代 T 细胞和 T 细胞，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 NF-κB 的协同作用。 3) 通过测量将 NF-kappaB 活性的反式显性 IkappaB 抑制子转导至 Th1/Tc1 和 Th2/Tc2 细胞克隆的效果，确定抑制 NF-kappaB 激活如何改变 T 细胞的表型和功能活性； 4)确定抑制树突状细胞中NF-κB激活对DC向Th1/Tc1和Th2/Tc2呈递抗原的能力的影响。将评估抑制树突状细胞中 NF-κB 激活对 Th1/Tc1 和 Th2/Tc2 细胞的激活、发育和效应功能的影响。这些结果将帮助我们更好地了解 T 细胞亚群在炎症反应期间如何发挥作用，并确定 Nf-kappaB 是否可以用作旨在控制 T 细胞炎症的治疗干预的靶点。