ROLE OF NF-KB IN T CELL INFLAMMATION

NF-KB 在 T 细胞炎症中的作用

• 批准号: 6644959
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6644959
• 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细胞种群中的1型和2型细胞的存在已得到充分记录。然而，关于导致这些表型T细胞和T细胞克隆的生成和维护的细胞信号通路的性质知之甚少。 NF-kappab是一个转录因子家族，在T淋巴细胞的激活和分化中已被证明至关重要。尽管NF-KAPPAB活性在CD8+ T细胞中的作用几乎一无所知，但似乎NF-KAPPAB在类型1与1型中被差异激活并调节。 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确定和维持其子集承诺方面起着关键作用。这些不同的激活条件包括通过T细胞受体，CD28和/或暴露于细胞因子IL-4和IL-12的刺激。该提案的目的是确定在TH1/TC1和TH2/TC2细胞亚集中调节NF-kappab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结果。我们计划到1）：通过评估TCR激活如何影响不同亚基的功能活性，评估T细胞受体（TCR）介导的1型CD4+和CD8+ T细胞的NF-KAPPAB的差异表达。 nf- kappab。通过确定原代T细胞和TCR在TCR中的NF-kappab激活NF-kappab激活的协同作用，通过确定原代T细胞和T细胞是否是由TCR激活。 3）确定NF-kappab激活的抑制是如何通过测量将NF-kappab活性转导转换型ikappab抑制剂到TH1/TC1和TH2/TC2细胞克隆中的跨主导IKAPPAB抑制剂来改变T细胞的表型和功能活性的； 4）确定树突状细胞中抑制NF-kappab激活对DC对TH1/TC1和TH2/TC2抗原的能力的影响。将评估树突状细胞中NF-kappab激活对Th1/Tc1和Th2/Tc2细胞的激活，发育和效应子功能的抑制作用。这些结果将有助于我们更好地理解T细胞子集在炎症反应过程中的功能，并确定是否可以将NF-KAPPAB用作旨在控制T细胞炎症的治疗干预措施的靶标。