Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease
Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease
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DOI：
10.1084/jem.20120058
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发表时间：
2012-09-24
影响因子：
15.3
通讯作者：
Love, Paul E.
中科院分区：
文献类型：
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作者：
Hwang, SuJin;Song, Ki-Duk;Love, Paul E.
负选择和调节性T（T reg）细胞发育是实施自身耐受所必需的两个胸腺依赖性过程，并且两者都需要T细胞受体（TCR）和自身配体之间的高亲和力相互作用。然而，目前尚不清楚它们是否受到TCR信号传导潜力改变的类似影响。我们产生了TCR ζ链基因的敲入等位基因（6 F），其编码缺乏信号传导能力的突变蛋白，其表达受内源性ζ调节序列控制。尽管6 F/6 F小鼠中的阴性选择是有缺陷的，导致自身反应性T细胞的存活，但6 F/6 F小鼠没有发展自身免疫性疾病。我们发现，6 F/6 F小鼠产生的胸腺来源的T reg细胞数量增加。我们表明，TCR信号传导潜力的衰减选择性地影响下游信号传导反应，这种差异效应有利于Foxp 3表达和T reg细胞谱系定型。这些结果确定了一种潜在的补偿途径，用于响应于由TCR信号传导能力降低引起的缺陷性阴性选择而实施免疫耐受。
Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR zeta chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous zeta regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability.