Abacavir inhibits but does not cause self-reactivity to HLA-B*57:01-restricted EBV specific T cell receptors.
Abacavir inhibits but does not cause self-reactivity to HLA-B*57:01-restricted EBV specific T cell receptors.
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DOI：
10.1038/s42003-022-03058-9
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发表时间：
2022-02-16
影响因子：
5.9
通讯作者：
Redwood AJ
中科院分区：
文献类型：
--
作者：
Sooda A;Rwandamuriye F;Wanjalla CN;Jing L;Koelle DM;Peters B;Leary S;Chopra A;Calderwood MA;Mallal SA;Pavlos R;Watson M;Phillips EJ;Redwood AJ
预先存在的病原体特异性记忆T细胞应答可导致多种不良结果，包括自身免疫和药物超敏反应。在许多这些疾病中，T细胞受体（TCR）的特异性如何被颠覆或辅助仍不清楚。在这里，我们应用阿巴卡韦超敏反应（AHS）作为模型来解决这个问题，因为这种疾病与记忆T细胞反应和HLA风险等位基因HLA-B*57：01和起始损伤阿巴卡韦是已知的。为了研究病原体特异性TCR特异性在介导AHS中的作用，我们对人类最普遍的病原体之一Epstein-Barr病毒（EBV）的HLA-B*57：01限制性T细胞应答进行了全基因组筛选。T细胞表位定位显示HLA-B*57：01限制性应答17个EBV开放阅读框，并鉴定了由EBNA 3C编码的表位。使用这些数据，我们克隆了EBNA 3C的显性TCR和EBNA 3B内先前定义的表位。确认了TCR对每个表位的特异性，然而，克隆的TCR不与阿巴卡韦加自身肽交叉反应。然而，阿巴卡韦抑制TCR与其同源配体的相互作用，表明TCR特异性可能被药物分子破坏。这些结果为未来研究TCR的异源免疫应答（包括T细胞介导的药物不良反应）提供了实验路线图。阿巴卡韦改变了HLA-B*57：01限制的EBV特异性T细胞受体特异性，表明阿巴卡韦对HLA-B*57：01限制的TCR识别具有潜在的抑制作用。
Pre-existing pathogen-specific memory T cell responses can contribute to multiple adverse outcomes including autoimmunity and drug hypersensitivity. How the specificity of the T cell receptor (TCR) is subverted or seconded in many of these diseases remains unclear. Here, we apply abacavir hypersensitivity (AHS) as a model to address this question because the disease is linked to memory T cell responses and the HLA risk allele, HLA-B*57:01, and the initiating insult, abacavir, are known. To investigate the role of pathogen-specific TCR specificity in mediating AHS we performed a genome-wide screen for HLA-B*57:01 restricted T cell responses to Epstein-Barr virus (EBV), one of the most prevalent human pathogens. T cell epitope mapping revealed HLA-B*57:01 restricted responses to 17 EBV open reading frames and identified an epitope encoded by EBNA3C. Using these data, we cloned the dominant TCR for EBNA3C and a previously defined epitope within EBNA3B. TCR specificity to each epitope was confirmed, however, cloned TCRs did not cross-react with abacavir plus self-peptide. Nevertheless, abacavir inhibited TCR interactions with their cognate ligands, demonstrating that TCR specificity may be subverted by a drug molecule. These results provide an experimental road map for future studies addressing the heterologous immune responses of TCRs including T cell mediated adverse drug reactions. HLA-B*57:01 restricted EBV-specific T-cell receptor specificity is altered by abacavir, suggesting a potentially inhibitory effect of abacavir on HLA-B*57:01 restricted TCR recognition.
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