Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice
Impaired responsiveness to T-cell receptor stimulation and defective negative selection of thymocytes in CCR7-deficient mice
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DOI：
10.1182/blood-2007-01-070284
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Foerster, Reinhold
中科院分区：
文献类型：
--
作者：
Davalos-Misslitz, Ana C. M.;Worbs, Tim;Foerster, Reinhold
趋化因子受体CCR 7与胸腺形态的维持和对自身抗原耐受性的建立有关。在这项研究中，我们提供了直接的证据，阴性选择成熟的胸腺细胞是有缺陷的CCR 7缺陷小鼠。在体内和体外TCR/CD 3复合物刺激后观察到阴性选择受损，并且在双阳性和半成熟单阳性细胞（CD 4（+）CD 8（-）CD 24（高））中均显著。值得注意的是，CCR 7（-/-）小鼠的胸腺细胞在对内源性超抗原的应答中显示出有缺陷的负选择，表明该缺陷也发生在生理条件下。干扰的阴性选择与体外TCR/CD 3刺激后CCR 7（-/-）胸腺细胞的激活动力学延迟和钙通量反应降低相关，这表明通过TCR介导的信号传导的CCR 7（-/-）胸腺细胞反应受损是这些小鼠中有缺陷的阴性选择的原因。
The chemokine receptor CCR7 has been implicated in maintenance of thymus morphology and establishment of tolerance to self-antigens. In this study, we provide direct evidence that negative selection of maturing thymocytes is defective in CCR7-deficent mice. Impaired negative selection was observed after TCR/CD3 complex stimulation in vivo as well as in vitro and was prominent in both double-positive and semimature single positive cells (CD4(+)CD8(-)CD24(high)). It is noteworthy that thymocytes of CCR7(-/-) mice display defective negative selection in response to endogenous superantigens, demonstrating that the defect also occurs under physiological conditions. Disturbed negative selection was correlated with delayed activation kinetics and decreased calcium flux response of CCR7(-/-) thymocytes after in vitro TCR/CD3 stimulation, suggesting that an impaired response of CCR7(-1-) thymocytes via TCR-mediated signaling is responsible for defective negative selection in these mice.