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.
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