生物谷综合: 追求长寿的人们一定不会想到,身体里的免疫细胞要是异常地“高寿”,就可能导致免疫系统攻击自身器官的“内乱”发生。最近,上海科学家发现了一种名叫β-arrestin1的蛋白(简称β蛋白)在生命体内诱导着这样一场混乱。今天凌晨出版的国际重要学术期刊《自然·免疫学》杂志刊登了这一最新成果。
按照正常的生命进程,当人体的先天免疫系统抵御不了病毒、细菌等“外敌”时,会向CD4+T细胞发出求救信号,让它赶紧征召各类获得性免疫细胞投入“保卫战”。战斗结束后,CD4+T细胞就会自动“卸任”———在外周免疫系统中凋亡。
中科院上海生科院生物化学和细胞生物学研究所裴钢院士研究组和中科院上海生科院/上海交大医学院健康科学研究所臧敬五教授研究组经过长期合作发现,当大量β蛋白出现在CD4+T细胞中,这种细胞就像吃了长生不老药一样,突然长寿起来———即使在完成任务后,也不凋亡。尽管大多数的CD4+T细胞会安分地颐养天年,但其中能攻击自身器官的“野心家”则得到了蠢蠢欲动的机会。一旦受到环境影响,或基因变异,这些“野心家”就会钻起防范机制出现的“漏洞”,逃离监管,征召懵懵懂懂的免疫细胞,攻击自身器官,造成自身免疫疾病,如多发性硬化并红斑狼疮等。
“我们已为这个成果申请了专利。”裴钢院士告诉记者,这个研究揭示出生物体内调节CD4+T细胞凋亡和自身免疫的新机制,并提示β蛋白有可能成为研发自身免疫治疗药物的新靶点。
原始出处:
Nature Immunology
Published online: 8 July 2007 | doi:10.1038/ni1489
Critical regulation of CD4+ T cell survival and autoimmunity by -arrestin 1
Yufeng Shi1, Yan Feng2, Jiuhong Kang1, Chang Liu1, Zhenxin Li3, Dangsheng Li4, Wei Cao2, Ju Qiu2, Zhengliang Guo5, Enguang Bi1, Lei Zang1, Chuanzhen Lu3, Jingwu Z Zhang2,5,6 & Gang Pei1
Abstract
CD4+ T cells are important in adaptive immunity, but their dysregulation can cause autoimmunity. Here we demonstrate that the multifunctional adaptor protein -arrestin 1 positively regulated naive and activated CD4+ T cell survival. We found enhanced expression of the proto-oncogene Bcl2 through -arrestin 1–dependent regulation of acetylation of histone H4 at the Bcl2 promoter. Mice deficient in the gene encoding -arrestin 1 (Arrb1) were much more resistant to experimental autoimmune encephalomyelitis, whereas overexpression of Arrb1 increased susceptibility to this disease. CD4+ T cells from patients with multiple sclerosis had much higher Arrb1 expression, and 'knockdown' of Arrb1 by RNA-mediated interference in those cells increased apoptosis induced by cytokine withdrawal. Our data demonstrate that -arrestin 1 is critical for CD4+ T cell survival and is a factor in susceptibility to autoimmunity.