Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity
Scalable signaling mediated by T cell antigen receptor-CD3 ITAMs ensures effective negative selection and prevents autoimmunity
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DOI：
10.1038/ni.1611
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发表时间：
2008-06-01
影响因子：
30.5
通讯作者：
Vignali, Dario A. A.
中科院分区：
文献类型：
--
作者：
Holst, Jeff;Wang, Haopeng;Vignali, Dario A. A.
T细胞抗原受体（TCR）-CD 3复合物的独特之处在于具有十个基于胞质免疫受体酪氨酸的激活基序（ITAM）。这种高TCR ITAM数的生理重要性尚不清楚。在这里，我们产生了25组小鼠表达野生型和突变ITAM的各种组合的TCR-CD 3复合物。少于7个野生型CD 3 ITAM的小鼠发展为致命的多器官自身免疫性疾病，其由中枢耐受性而不是外周耐受性的破坏引起。虽然野生型CD 3 ITAM的数量和T细胞增殖之间存在线性相关性，但细胞因子的产生不受ITAM数量的影响。因此，高ITAM数提供了可调节增殖但确保有效的阴性选择和自身免疫预防的可扩展信号传导。
The T cell antigen receptor (TCR)-CD3 complex is unique in having ten cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). The physiological importance of this high TCR ITAM number is unclear. Here we generated 25 groups of mice expressing various combinations of wild-type and mutant ITAMs in TCR-CD3 complexes. Mice with fewer than seven wild-type CD3 ITAMs developed a lethal, multiorgan autoimmune disease caused by a breakdown in central rather than peripheral tolerance. Although there was a linear correlation between the number of wild-type CD3 ITAMs and T cell proliferation, cytokine production was unaffected by ITAM number. Thus, high ITAM number provides scalable signaling that can modulate proliferation yet ensure effective negative selection and prevention of autoimmunity.