OBJECTIVES Cellular immunity against BK polyomavirus (BKV)-encoded antigens plays a crucial role in long-term protection against virus-associated pathogenesis in transplant recipients. However, in-depth understanding on dynamics of these cellular immune responses is required to develop better immune monitoring and immunotherapeutic strategies. METHODS Here, we have conducted a proteome-wide analysis of BKV-specific T-cell responses in a cohort of 53 healthy individuals and 26 kidney transplant recipients to delineate the functional and transcriptional profile of these effector cells and compared these characteristics to T cells directed against cytomegalovirus, which is also known to cause significant morbidity in transplant recipients. RESULTS Profiling of BKV-specific CD4+ and CD8+ T cells revealed that kidney transplant recipients with high levels of circulating viraemia showed significantly reduced T-cell reactivity against large T and/or small T antigens when compared to healthy donors. Interestingly, T cells specific for these antigens showed strong cross-recognition to orthologous JC virus (JCV) peptides, including those exhibiting varying degrees of sequence identity. Ex vivo functional and phenotypic characterisation revealed that the majority of BKV-specific T cells from renal transplant recipients expressed low levels of the key transcriptional regulators T-bet and eomesodermin, which was coincident with undetectable expression of granzyme B and perforin. However, in vitro stimulation of T cells with BKV epitopes selectively enhanced the expression of T-bet, granzyme B and cellular trafficking molecules (CCR4, CD49d and CD103) with minimal change in eomesodermin and perforin. CONCLUSIONS These observations provide an important platform for the future development of immune monitoring and adoptive T-cell therapy strategies for BKV-associated diseases in transplant recipients, which may also be exploited for similar therapeutic value in JCV-associated clinical complications.

中文翻译：

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对健康病毒携带者和肾移植受者中 T 细胞对 BK 多瘤病毒反应的全蛋白质组分析揭示了独特的转录和功能特征。

目的 针对 BK 多瘤病毒 (BKV) 编码抗原的细胞免疫在长期保护移植受者免受病毒相关发病机制中起关键作用。然而，需要深入了解这些细胞免疫反应的动态，以开发更好的免疫监测和免疫治疗策略。方法 在这里，我们对 53 名健康个体和 26 名肾移植受者的 BKV 特异性 T 细胞反应进行了全蛋白质组分析，以描绘这些效应细胞的功能和转录谱，并将这些特征与 T 细胞定向进行比较抗巨细胞病毒，这也是已知的在移植受者中引起显着发病率的病毒。结果 BKV 特异性 CD4+ 和 CD8+ T 细胞的分析显示，与健康供体相比，具有高水平循环病毒血症的肾移植受者对大 T 和/或小 T 抗原的 T 细胞反应性显着降低。有趣的是，对这些抗原特异的 T 细胞显示出对直系同源 JC 病毒 (JCV) 肽的强烈交叉识别，包括那些表现出不同程度的序列同一性的肽。离体功能和表型表征表明，来自肾移植受者的大多数 BKV 特异性 T 细胞表达低水平的关键转录调节因子 T-bet 和中胚层，这与颗粒酶 B 和穿孔素的不可检测表达一致。然而，用 BKV 表位体外刺激 T 细胞选择性地增强了 T-bet 的表达，粒酶 B 和细胞运输分子（CCR4、CD49d 和 CD103）在中胚层和穿孔素中的变化很小。结论 这些观察结果为移植受者 BKV 相关疾病的免疫监测和过继性 T 细胞治疗策略的未来发展提供了重要平台，也可用于 JCV 相关临床并发症的类似治疗价值。