Increased threshold for TCR-mediated signaling controls self reactivity of intraepithelial lymphocytes.
Increased threshold for TCR-mediated signaling controls self reactivity of intraepithelial lymphocytes.
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DOI：
10.4049/jimmunol.160.11.5341
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发表时间：
1998-06
影响因子：
4.4
通讯作者：
S. R. Guehler;R. J. Finch;J. Bluestone;T. Barrett
中科院分区：
文献类型：
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作者：
S. R. Guehler;R. J. Finch;J. Bluestone;T. Barrett
为了研究自身抗原对TCR-α肠上皮内淋巴细胞（IEL）活化要求的影响，我们利用了对由I类MHC（H-2Ld）呈递的肽自身抗原特异性的2C转基因（Tg）小鼠模型。检测了来自同源（H-2b，自身Ag-）和自身Ag携带（H-2b/d，自身Ag+）菌株的CD 8 α α和CD 4-CD 8-IEL对表达内源性抗原肽p2Ca的P815（H-2d）细胞系的体外应答能力。当用表达基础水平自身Ag的P815细胞刺激时，在从自身Ag-H-2b小鼠分离的IEL T细胞中引发增殖、细胞因子产生和CTL活性。这些反应增强后，加入外源性p2Ca肽和异位表达的共刺激分子，B7-1。相比之下，IEL从自身Ag荷瘤小鼠未能响应由P815细胞，即使在B7-1介导的共刺激的存在下的自身Ag的基础水平。然而，增加量的外源性p2Ca肽的添加诱导了来自体内“耐受化”T细胞的应答。这些结果表明，在体内暴露于自身Ag增加了暴露于Ag的自身反应性IEL的TCR活化的阈值。增加的信号1激活自身反应性IEL的依赖性表明TCR信号传导中的缺陷可能维持体内的自身耐受。这些数据表明，克服信号1 IEL缺陷的条件下，可能会启动肠中的自身反应性反应。
To examine the effect of self Ag on activation requirements of TCR-alphabeta intestinal intraepithelial lymphocytes (IELs), we utilized the 2C transgenic (Tg) mouse model specific for a peptide self Ag presented by class I MHC, H-2Ld. CD8alpha alpha and CD4-CD8- IELs from syngeneic (H-2b, self Ag-) and self Ag-bearing (H-2b/d, self Ag+) strains were examined for their ability to respond in vitro to P815 (H-2d) cell lines expressing the endogenous antigenic peptide, p2Ca. Proliferation, cytokine production, and CTL activity were elicited in IEL T cells isolated from self Ag- H-2b mice when stimulated with P815 cells expressing basal levels of self Ag. These responses were enhanced following the addition of exogenous p2Ca peptide and ectopic expression of the costimulatory molecule, B7-1. By comparison, IEL from self Ag-bearing mice failed to respond to basal levels of self Ag presented by P815 cells even in the presence of B7-1-mediated costimulation. However, the addition of increasing amounts of exogenous p2Ca peptide induced a response from the in vivo "tolerized" T cells. These results suggest that exposure to self Ag in vivo increased the threshold of TCR activation of Ag-exposed self-reactive IELs. The dependence of increased signal 1 to activate self-reactive IELs suggests a defect in TCR signaling that may maintain self tolerance in vivo. These data suggest that conditions that overcome signal 1 IEL defects may initiate autoreactive responses in the intestine.