ZAP70, too little, too much can lead to autoimmunity.
ZAP70, too little, too much can lead to autoimmunity.
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DOI：
10.1111/imr.13058
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发表时间：
2022-05
影响因子：
8.7
通讯作者：
Weiss A
中科院分区：
文献类型：
--
作者：
Ashouri JF;Lo WL;Nguyen TTT;Shen L;Weiss A
建立中枢和外周耐受需要适当的TCR信号强度来区分自身与与自身MHC分子结合的激动剂肽。ZAP70是一种细胞质酪氨酸激酶，直接与TCR复合物相互作用，在胸腺细胞和外周T细胞的TCR信号传导中起着核心和必要的作用。通过研究具有低活性或多活性的小鼠和人类的ZAP70亚型突变，我们已经深入了解了中枢和外周耐受性的机制。有趣的是，尽管通过不同的机制，但低活性和高活性的ZAP70都可以导致自身免疫性疾病的发展。未成熟的胸腺细胞和成熟的T细胞依靠正常的ZAP70功能来完成它们在胸腺中的发育，并调节周围的T细胞反应。低活性的ZAP70功能损害了建立中枢耐受性所需的关键发育检查点，使具有潜在自我反应性tcr的胸腺细胞有更大的机会逃避负选择。这种“禁止克隆”可能会逃逸到外周，并可能对自身免疫性疾病的发展造成更大的风险，因为它们可能无法有效地参与负面调节机制。过度活跃的ZAP70增强了胸腺的负选择，但一些胸腺细胞会逃避负选择，对弱配体和自身配体更敏感。这些细胞必须受到与能量、treg扩增、抑制受体或信号分子上调有关的机制的控制。然而，这种潜在的自身反应性细胞可能仍然能够逃脱外周负调控约束的控制。与在Zap70突变体中的发现一致，至少一种Zap70底物LAT的信号缺陷也可导致自身免疫性疾病。通过剖析影响TCR信号强度的患者疾病或ZAP70突变小鼠模型的异同，我们已经深入了解了ZAP70功能紊乱如何导致自身免疫。由于我们和其他人对ZAP70的研究，可能会发现影响TCR信号强度的其他分子的扰动也会克服耐受性机制并引起自身免疫。描述这些分子途径可能导致这些复杂疾病急需新的治疗靶点的发展。
Establishing both central and peripheral tolerance requires the appropriate TCR signaling strength to discriminate self‐ from agonist‐peptide bound to self MHC molecules. ZAP70, a cytoplasmic tyrosine kinase, directly interacts with the TCR complex and plays a central and requisite role in TCR signaling in both thymocytes and peripheral T cells. By studying ZAP70 hypomorphic mutations in mice and humans with a spectrum of hypoactive or hyperactive activities, we have gained insights into mechanisms of central and peripheral tolerance. Interestingly, both hypoactive and hyperactive ZAP70 can lead to the development of autoimmune diseases, albeit through distinct mechanisms. Immature thymocytes and mature T cells rely on normal ZAP70 function to complete their development in the thymus and to modulate T cell responses in the periphery. Hypoactive ZAP70 function compromises key developmental checkpoints required to establish central tolerance, allowing thymocytes with potentially self‐reactive TCRs a greater chance to escape negative selection. Such ‘forbidden clones’ may escape into the periphery and may pose a greater risk for autoimmune disease development since they may not engage negative regulatory mechanisms as effectively. Hyperactive ZAP70 enhances thymic negative selection but some thymocytes will, nonetheless, escape negative selection and have greater sensitivity to weak and self‐ligands. Such cells must be controlled by mechanisms involved in anergy, expansion of Tregs, and upregulation of inhibitory receptors or signaling molecules. However, such potentially autoreactive cells may still be able to escape control by peripheral negative regulatory constraints. Consistent with findings in Zap70 mutants, the signaling defects in at least one ZAP70 substrate, LAT, can also lead to autoimmune disease. By dissecting the similarities and differences among mouse models of patient disease or mutations in ZAP70 that affect TCR signaling strength, we have gained insights into how perturbed ZAP70 function can lead to autoimmunity. Because of our work and that of others on ZAP70, it is likely that perturbations in other molecules affecting TCR signaling strength will be identified that also overcome tolerance mechanisms and cause autoimmunity. Delineating these molecular pathways could lead to the development of much needed new therapeutic targets in these complex diseases.
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