ROLE OF NF-KB IN T CELL INFLAMMATION

在CD4+和CD8+ T细胞群中存在1型和2型细胞已被充分证明。然而，人们对导致这些表型T细胞和T细胞克隆产生和维持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，已被证明在T淋巴细胞的激活和分化中起重要作用。虽然NF-kappaB活性在CD8+ T细胞中的作用几乎一无所知，但NF-kappaB在1型和1型T细胞中的激活和调节似乎是不同的。2型CD4+ T细胞克隆。我们假设，调节转录因子NF-kappaB的激活条件差异有助于T细胞向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中起关键作用。这些不同的激活条件包括T细胞受体、CD28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-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)：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，通过评估TcR激活如何影响不同亚单位的功能活性。NF- κ b。通过测定原代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活化NF-kappaB的协同作用。3)通过测量将NF-kappaB的反显性IkappaB抑制因子转导到Th1/Tc1和Th2/Tc2细胞克隆中的效果，确定NF-kappaB活化的抑制如何改变T细胞的表型和功能活性；4)确定抑制树突状细胞NF- kappaB活化对DC向Th1/Tc1和Th2/Tc2递呈抗原能力的影响。我们将评估抑制树突状细胞中NF-kappaB活化对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中的功能，并确定Nf-kappaB是否可以作为治疗干预的靶标，用于控制T细胞炎症。

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.