Siggs Owen M, Miosge Lisa A, Yates Adèle L, Kucharska Edyta M, Sheahan Daniel, Brdicka Tomas, Weiss Arthur, Liston Adrian, Goodnow Christopher C
John Curtin School of Medical Research and Australian Phenomics Facility, The Australian National University, Canberra 2601, Australia.
Immunity. 2007 Dec;27(6):912-26. doi: 10.1016/j.immuni.2007.11.013.
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 pleiotropic functions of ZAP-70 and their differential response to graded variation provide a paradigm for understanding the complex outcomes of human genetic variation.
使T细胞受体（TCR）信号传导受损的无效突变可解释罕见的原发性免疫缺陷，但尚不清楚为何导致TCR信号传导细微缺陷的更常见多态性反而与自身免疫相关。在此，我们分析了一系列TCR信号传导呈逐步减弱的Zap70变体如何影响免疫和耐受这两种相反的TCR功能。一种Zap70变体，即默多克变体，适度降低了TCR信号传导和胸腺选择，而不影响免疫耐受，而更严重的Zap70缺陷，即无髓变体，则消除了胸腺阳性选择并导致免疫缺陷。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Foxp3(+)调节性T细胞的形成，在免疫原性和耐受性功能之间造成细胞失衡，导致自身抗体和免疫球蛋白E（IgE）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。
