HLA Class-II‒Restricted CD8+ T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients
HLA Class-II‒Restricted CD8+ T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients
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HLA-II 类限制性 CD8 T 细胞导致氨苯砜过敏患者出现混杂的免疫反应
DOI：
10.1016/j.jid.2021.03.014
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发表时间：
2021
影响因子：
6.5
通讯作者：
Hong Li
中科院分区：
文献类型：
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作者：
Qing Zhao;Mubarak Almutairi;Arun Tailor;Adam Lister;Nicolas Harper;James Line;Xiaoli Meng;Jirawat Pratoomwun;Kanoot Jaruthamsophon;Chonlaphat Sukasem;Yonghu Sun;Lele Sun;Monday O. Ogese;David J. MacEwan;Munir Pirmohamed;Jianjun Liu;David A. Ostrov;Hong Li
HLA-B*13:01 与氨苯砜 (DDS) 诱导的超敏反应相关，并且已表明 CD4+ 和 CD8+ T 细胞被 DDS 及其亚硝基代谢物（亚硝基氨苯砜 [DDS-NO]）激活。然而，需要明确 HLA 关联在疾病发病机制中的重要性。因此，从表达 HLA-B*13:01 的过敏患者中产生 DDS 和 DDS-NO 特异性 CD8+ T 细胞克隆 (TCC)，并对其表型和功能、HLA 等位基因限制和靶细胞杀伤进行评估。当暴露于 DDS 和/或 DDS-NO 时，CD8+ TCC 被刺激增殖并分泌效应分子。表达多种 TCR 序列的 DDS 响应性和几个 DDS-NO 响应性 TCC 表现出 HLA I 类限制，药物（代谢物）与多个 HLA-B 等位基因相互作用。然而，某些 DDS-NO 反应性 CD8+ TCC 的激活受到 HLA II 类阻断的抑制，DDS-NO 与 HLA-DQB1*05:01 结合。这些 TCC 来源不同，但表达的 TCR 具有相同的氨基酸序列。它们通过半抗原途径被激活；展示CD45RO、CD28、PD-1和CTLA-4表面分子；分泌与 HLA I 类限制性 TCC 相同的效应分子组；但表现出较低的裂解靶细胞的能力。总之，DDS 和 DDS-NO 与许多 HLA 分子相互作用，激活 CD8+ TCC，而显示出混合 CD4-CD8 特征的 HLA II 类限制性 CD8+ TCC 也有助于患者产生混杂的免疫反应。
HLA-B∗13:01 is associated with dapsone (DDS)-induced hypersensitivity, and it has been shown that CD4+ and CD8+ T cells are activated by DDS and its nitroso metabolite (nitroso dapsone [DDS-NO]). However, there is a need to define the importance of the HLA association in the disease pathogenesis. Thus, DDS- and DDS-NO‒specific CD8+ T-cell clones (TCCs) were generated from hypersensitive patients expressing HLA-B∗13:01 and were assessed for phenotype and function, HLA allele restriction, and killing of target cells. CD8+ TCCs were stimulated to proliferate and secrete effector molecules when exposed to DDS and/or DDS-NO. DDS-responsive and several DDS-NO‒responsive TCCs expressing a variety of TCR sequences displayed HLA class-I restriction, with the drug (metabolite) interacting with multiple HLA-B alleles. However, activation of certain DDS-NO‒responsive CD8+ TCCs was inhibited with HLA class-II block, with DDS-NO binding to HLA-DQB1∗05:01. These TCCs were of different origin but expressed TCRs displaying the same amino acid sequences. They were activated through a hapten pathway; displayed CD45RO, CD28, PD-1, and CTLA-4 surface molecules; secreted the same panel of effector molecules as HLA class-I‒restricted TCCs; but displayed a lower capacity to lyse target cells. To conclude, DDS and DDS-NO interact with a number of HLA molecules to activate CD8+ TCCs, with HLA class-II‒restricted CD8+ TCCs that display hybrid CD4‒CD8 features also contributing to the promiscuous immune response that develops in patients.