ROLE OF NF-KB IN T CELL INFLAMMATION

NF-KB 在 T 细胞炎症中的作用

• 批准号: 6654111
• 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: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654111
• 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CD 4+和CD 8 + T细胞群中存在1型和2型细胞已被充分证明。然而，很少有人知道，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。NF-κ B是一个转录因子家族，已被证明在T淋巴细胞的活化和分化中具有重要意义。虽然实际上对NF-κ B活性在CD 8 + T细胞中的作用一无所知，但似乎NF-κ B在1型T细胞中与在2型T细胞中被差异活化和调节。2型CD 4 + T细胞克隆。我们假设，差异调节转录因子NF-κ B的活化条件有助于T细胞向Th 1/Tc 1或Th 2/Tc 2细胞谱系的承诺，并且这种差异调节在确定和维持其亚群承诺中起着关键作用。这些不同的活化条件包括通过T细胞受体、通过CD 28和/或暴露于细胞因子IL-4和IL-12的刺激。本提案的目的是确定NF-κ B在Th 1/Tc 1和Th 2/Tc 2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介导的活化如何影响不同亚基的功能活性，评估NF-κ B在T细胞受体（TcR）介导的1型和2型CD 4+和CD 8 + T细胞活化中的差异表达。NF-κ B的表达。通过确定原代T细胞和T细胞克隆中是否存在TcR来确定细胞因子和共刺激对原代T细胞和T细胞克隆中NF-κ B活化的协同作用。3)通过测量将NF-κ B活性的反式显性IkappaB阻遏物转导到Th 1/Tc 1和Th 2/Tc 2细胞克隆中的作用，确定NF-κ B活化的抑制如何改变T细胞的表型和功能活性;和4）确定抑制树突状细胞中NF-κ B活化对DC将抗原呈递给Th 1/Tc 1和Th 2/Tc 2的能力的作用。将评估树突状细胞中NF-κ B活化的抑制对Th 1/Tc 1和Th 2/Tc 2细胞的活化、发育和效应子功能的影响。这些结果将帮助我们更好地了解T细胞亚群在炎症反应中的功能，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。