Control of immunological tolerance and its breakdown by cytokine

白细胞介素-2（IL-2）是T细胞生长因子，在免疫应答的扩增和维持中起重要作用。IL-2缺陷小鼠发生与人类溃疡性结肠炎相似的结肠炎。炎症性疾病的特征在于大量活化的T和B细胞和升高的免疫球蛋白分泌，表明该疾病是由对正常抗原刺激的异常免疫应答引起的。另一方面，抑制IL-2作用的免疫抑制剂通常改善各种自身免疫性疾病。因此，IL-2信号转导功能障碍或异常激活直接影响免疫耐受。在此背景下，我们研究了T细胞生长和IL-2抑制生长的分子机制，以阐明自身免疫性疾病的基本机制。1）建立了以TPA-Mat、IL-2和TPA依赖性T细胞为筛选对象的IL-2信号转导分子的筛选体系。2）AICD可导致MT-1β的凋亡。3)Mkk 3 ^<-/->、Mkk 6 ^<-/->和野生型小鼠IL-2依赖性T细胞增殖无显著差异，但Mkk 3 ^<-/->小鼠T细胞对IL-2戒断诱导的凋亡具有更强的抵抗性。4)Mkk 3和Mkk 6在胚胎发生过程中的损失是致命的胚胎天E11.5之前。观察到胎盘、心脏形成的主要缺陷和胚胎脉管系统发育的缺陷。特别是，迷路和海绵滋养层显着减少的突变体与野生型相比。TNF-α不刺激p38 MAPK的激活。紫外线辐射引起了Mkk 3 ^<-/->和Mkk 6 ^<-/->小鼠细胞中p38 MAPK的激活，尽管与野生型细胞相比，p38 MAPK的激活程度有所降低。

Interleukin-2 (IL-2), which was identified as T cell growth factor, plays a important role of the expansion and maintenance in immune response. IL-2-deficient-mice developed colonic inflamation closely resemblling ulcerative colitis in human. The inflamatory disease is characterized by high number of activated T and B cells and elevated immunoglobulin secretion, suggesting that the disease results from an abnormal immune response to a normal antigenic stimulus. On the other hand, immunosuppressive agents, which suppress the effects of IL-2, usually improve various autoimmune disorders. Therefore dysfunction or unusual activation in IL-2 signal transduction has influence on immunological tolerance directly. In this context, we have investigated the molecular machinery of the T cell growth and growth suppression by IL-2 to elucidate the basal mechanism of autoimmune disease. 1)we have established the screening system for the molecule(s) that involved in IL-2 signal transduction using the TPA-Mat, IL-2 and TPA dependent T cell line. 2)we found that the apoptosis of MT-1β resulted from AICD. 3) Although there was no significant difference in IL-2 dependent T cell proliferation among Mkk3^<-/->,Mkk6^<-/-> and wild type mice, the T cells from Mkk3^<-/-> mice were more resistant to apoptosis induced by IL-2 withdrawal. 4)The loss of Mkk3 and Mkk6 during embryogenesis was lethal before embryonic day E11.5. Major defects in the formation of the placenta, heart and deficiencies in the development of the embryonic vasculature were observed. Especially, the labyrinth and spongiotrophoblast layers were markedly decreased in the mutant compared with the wild type. TNF-α did not stimulate activation of p38 MAPK. UV radiation caused p38 MAPK activation in the cells from Mkk3^<-/-> and Mkk6^<-/-> mice, although the extent of p38 MAPK activation was diminished compared with wild-type cells.