Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions
Opposing functions of the T cell receptor kinase ZAP-70 in immunity and tolerance differentially titrate in response to nucleotide substitutions
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DOI：
10.1016/j.immuni.2007.11.013
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发表时间：
2007-12-01
期刊：
影响因子：
32.4
通讯作者：
Goodnow, Christopher C.
中科院分区：
文献类型：
--
作者：
Siggs, Owen M.;Miosge, Lisa A.;Goodnow, Christopher C.
削弱T细胞受体（TCR）信号传导的突变解释了罕见的原发性免疫缺陷，但目前尚不清楚为什么更常见的多态性，导致微妙的TCR信号传导缺陷是矛盾的与自身免疫。在这里，我们分析了一系列Zap 70变体在TCR信号传导中的逐步减少如何影响免疫和耐受的相反TCR功能。一种Zap 70变体，默多克，适度降低TCR信号传导和胸腺选择，而不损害免疫耐受，而更严重的Zap 70缺陷，mrtless，取消胸腺阳性选择，导致免疫缺陷。这两个阈值之间的信号传导能力不成比例地损害了阴性选择和Foxp 3（+）调节性T细胞的形成，在免疫原性和致耐受性功能之间产生细胞失衡，导致自身抗体和免疫球蛋白E（IgE）的过度产生。ZAP-70的多效性功能及其对分级变异的不同反应为理解人类遗传变异的复杂结果提供了一个范例。
Null mutations that cripple T cell receptor (TCR) signaling explain rare primary immunodeficiencies, but it is not understood why more common polymorphisms that lead to subtle TCR signaling defects are paradoxically associated with autoimmunity. Here we analyzed how a series of Zap70 variants with step-wise decreases in TCR signaling impacted upon opposing TCR functions of immunity and tolerance. One Zap70 variant, murdock, moderately decreased TCR signaling and thymic selection without compromising immunological tolerance, whereas a more severe Zap70 defect, mrtless, abolished thymic-positive selection and led to immunodeficiency. Signaling capacities between these two thresholds disproportionately compromised negative selection and Foxp3(+) regulatory T cell formation, creating a cellular imbalance between immunogenic and tolerogenic functions that resulted in the excessive production of autoantibodies and immunoglobulin E (IgE). The pleictropic functions of ZAP-70 and their differential response to graded variation provide a paradigm for understanding the complex outcomes of human genetic variation.