Control of immunological tolerance and its breakdown by cytokine

白细胞介素2(IL-2)被认为是T细胞生长因子，在免疫应答的扩增和维持中起着重要作用。IL-2缺乏-小鼠的结肠炎与人类的溃疡性结肠炎非常相似。这种炎症性疾病的特点是激活的T和B细胞数量较多，免疫球蛋白分泌增加，这表明该病是由于对正常抗原刺激的异常免疫反应所致。另一方面，抑制IL-2作用的免疫抑制剂通常可以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IL-2抑制T细胞生长的分子机制，以阐明自身免疫性疾病的基本机制。1)利用TPA-MAT、IL-2和TPA依赖的T细胞系建立了参与IL-2信号转导的分子(S)的筛选体系。2)我们发现AICD可导致MT-1β的凋亡。3)MKK3^-lt；-/-&gt；、Mkk6；-/-&gt；-/-&gt；与野生型小鼠相比，IL-2依赖的T细胞增殖无显著差异，但MKK3；-/-&gt；-/-&gt；小鼠的T细胞对IL-2撤除诱导的凋亡有较强的抵抗力。4)胚胎发生过程中MKK3和MKK6的缺失在胚胎发育到E11.5天之前是致死的。观察到胎盘、心脏形成的主要缺陷和胚胎血管发育的缺陷。与野生型相比，突变体的迷路和海绵滋养层明显减少。肿瘤坏死因子-α不能刺激p38MAPK的激活。紫外线照射可引起MKK3^&lt；-/-&gt；和Mkk6^&lt；-/-&gt；小鼠细胞中p38 MAPK的激活，但与野生型细胞相比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.