NUCLEAR TRANSCRIPTION FACTOR ROLE IN T CELL ACTIVATION AND DISEASE

淋巴细胞和白细胞活化是保护 个人从疾病。 虽然最初的激活事件涉及 细胞表面受体，细胞的最终反应是介导的 通过核转录因子调节免疫相关基因， 效应子应答，例如编码细胞因子的那些基因。 NFkB和 已经发现IkB蛋白（调节NF κ B的活性）是 与编码蛋白质的基因的体外转录有关 参与免疫反应。 然而，它们与体内 生理反应是未知的。 对活动的干扰 这些因素对于理解和开发新的 移植物抗宿主病、炎症反应和 对病原体的反应。 为了了解在人类的生理作用 这些因子在淋巴细胞发育和对各种 在病原体中，缺乏Bcl-3（IkB家族）或p52（NFkB家族）的小鼠是 通过同源重组产生。 Bcl-3缺陷检测 小鼠的研究表明，淋巴细胞的发育似乎没有受到影响。 胸腺细胞和外周血T细胞明显，B细胞可在 这些动物。 然而，脾脏中的B/T细胞比率降低。 对感染流感病毒的Bcl-3-/-小鼠的分析表明， Bcl-3缺陷动物不能正常形成生殖中心， 对病毒的抗体反应减弱。 此外，感染小鼠 弓形虫，揭示了T细胞免疫缺陷。 Bcl-3缺陷 老鼠死于疾病， 产生Th 1细胞因子γ干扰素 虽然进一步的研究 需要，这些数据表明Bcl-3在疾病中起着关键作用， 通过调节细胞因子的产生来保护， 调节Th 1（促炎反应）与Th 2（更良性）T细胞 反应 未来的研究将致力于了解 Ik B和NF k B蛋白对T细胞、B细胞和单核细胞调节 activation.

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.