NUCLEAR TRANSCRIPTION FACTOR ROLE IN T CELL ACTIVATION AND DISEASE

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Lymphocyte and leucocyte activation are essential in protecting individuals from disease. While the initial activation events involve cell surface receptors, the ultimate response made by cells is mediated by nuclear transcription factors which regulate genes involved in immune effector responses, such as those genes encoding cytokines. The NFkB and IkB proteins (which regulate the activity of NFkB) have been found to be associated with the in vitro transcription of genes encoding proteins involved in immune responses. However, their relevance to in vivo physiologic responses is not known. Interference with the activity of these factors may be important for understanding and developing new treatments for graft vs host disease, inflmmatory reactions, and responses to pathogens. In order to understand the physiologic role these factors play in lymphocyte development and responses to a variety of pathogens, mice lacking Bcl-3 (IkB family) or p52 (NFkB family) were generated by homologous recombination. Examination of Bcl-3 deficient mice has revealed that lymphocyte development grossly appears unaffected. Thymocytes and peripheral T cellsare evident and B cells can be found in these animals. However, the B/T cell ratio in the spleen was reduced. Analyses of Bcl-3-/- mice infected with influenza virus demonstrated that Bcl-3 deficient animls do not form germinal centers normally and have an impaired antibody response to virus. Further, infection of mice with Toxoplasma gondii, revealed a defect in T cell immunity. Bcl-3 deficient mice succummed to disease and appeared to have a defict in their abiltiy to produce the the Th1 cytokine, gamma IFN. While further studies are required, these data suggest that Bcl-3 plays a crtical role in disease protection by regulating cytokine elaboration and may play a role in regulating the Th1 (proinflammatory response) vs Th2 (more benign) T cell response. Future studies will be directed at understanding the role of the IkB and NFkB proteins in regulating T cell, B cell and monocyte activation.