LOSS OF CTLA-4 LEADS TO MASSIVE LYMPHOPROLIFERATION AND FATAL MULTIORGAN TISSUE DESTRUCTION, REVEALING A CRITICAL NEGATIVE REGULATORY ROLE OF CTLA-4
LOSS OF CTLA-4 LEADS TO MASSIVE LYMPHOPROLIFERATION AND FATAL MULTIORGAN TISSUE DESTRUCTION, REVEALING A CRITICAL NEGATIVE REGULATORY ROLE OF CTLA-4
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DOI：
10.1016/1074-7613(95)90125-6
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发表时间：
1995-11-01
期刊：
影响因子：
32.4
通讯作者：
SHARPE, AH
中科院分区：
文献类型：
--
作者：
TIVOL, EA;BORRIELLO, F;SHARPE, AH
B7-CD28/CTLA-4共刺激通路可以为T细胞激活提供信号枢纽，由于存在B7家族的两个成员B7-1和B7-2，以及两个对抗性受体CD28和CTLA-4，通过该通路的信号转导是复杂的。抗CTLA-4单抗的研究表明，CTLA-4在T细胞活化中既有阳性作用，也有阴性作用，为了阐明CTLA-4在体内的功能，我们建立了CTLA-4缺陷小鼠。这些小鼠迅速发展为淋巴增殖性疾病，伴有多器官淋巴细胞渗透和组织破坏，并伴有特别严重的心肌炎和胰腺炎，并在3-4周大时死亡。CTLA-4缺陷小鼠品系的表型得到了研究的支持，这些研究表明CTLA-4在T细胞激活中起负面作用。缺乏CTLA-4的小鼠的严重表型暗示了CTLA-4在下调T细胞激活和维持免疫平衡方面的关键作用。在缺乏CTLA-4的情况下，外周T细胞被激活，可以自发增殖，并可能介导致命的组织损伤。
The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation, Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation, To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in downregulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.