DUAL T-CELL RECEPTOR ALPHA-CHAIN T-CELLS IN AUTOIMMUNITY
DUAL T-CELL RECEPTOR ALPHA-CHAIN T-CELLS IN AUTOIMMUNITY
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DOI：
10.1084/jem.182.4.953
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发表时间：
1995-10-01
影响因子：
15.3
通讯作者：
ALTMANN, DM
中科院分区：
文献类型：
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作者：
ELLIOTT, JI;ALTMANN, DM
T细胞受体α基因座TCR-α处的等位基因排斥是不完全的，如通过携带两种表达的α链产物的许多T淋巴细胞克隆的存在所证明的。已经提出这种双α链T细胞在自身免疫中起作用，例如，因为第二TCR-α β对凭借低表达绕过了阴性选择。我们通过产生携带TCR-α基因座的半合子靶向破坏的各种自身免疫倾向品系的小鼠来检验这一假设，因此不能产生双α链T细胞。正常小鼠具有低但显著比例的表达两个细胞表面TCR-α链的T细胞，其可以通过与没有TCR-α半合子相比来计数。对各种自身免疫性疾病的易感性在TCR-α半合子中进行了分析，所述半合子已经与疾病易感株回交了几代。实验性变态反应性脑脊髓炎和狼疮的发病率不受双TCR-α细胞缺乏的影响。相比之下，非肥胖糖尿病（NOD）TCR α半合子显着保护环磷酰胺加速胰岛炎和糖尿病。因此，双α T细胞可能在一些但不是所有的自身免疫性疾病中发挥重要作用。此外，由于受保护的和易感的NOD小鼠都显示出对谷氨酸脱羧酶的强烈自发反应，因此对该抗原的反应（如果糖尿病发生所必需的话）是不够的。
Allelic exclusion at the T cell receptor alpha locus TCR-alpha is incomplete, as demonstrated by the presence of a number of T lymphocyte clones carrying two expressed alpha chain products. Such dual alpha chain T cells have been proposed to play a role in autoimmunity, for example, because of a second TCR-alpha beta pair having bypassed negative selection by virtue of low expression. We examined this hypothesis by generating mice of various autoimmunity-prone strains carrying a hemizygous targeted disruption of the TCR-alpha locus, therefore unable to produce dual alpha chain T cells. Normal mice have a low but significant proportion of T cells expressing two cell-surface TCR-alpha chains that could be enumerated by comparison to TCR-alpha hemizygotes, which have none. Susceptibility to various autoimmune diseases was analyzed in TCR-alpha hemizygotes that had been backcrossed to disease-prone strains for several generations. The incidence of experimental allergic encephalomyelitis and of lupus is not affected by the absence of dual TCR-alpha cells. In contrast, nonobese diabetic (NOD) TCR alpha hemizygotes are significantly protected from cyclophosphamide-accelerated insulitis and diabetes. Thus, dual alpha T cells may play an important role in some but not all autoimmune diseases. Furthermore, since protected and susceptible NOD mice both show strong spontaneous responses to glutamic acid decarboxylase, responses to this antigen, if necessary for diabetetogenesis, are not sufficient.