Targeted Tumor Vaccines Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Targeted Tumor Vaccines Group, Clinical Cooperation Unit Applied Tumor Immunity, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
EBioMedicine. 2021 Oct;72:103610. doi: 10.1016/j.ebiom.2021.103610. Epub 2021 Oct 6.
Recent studies have provided evidence of T cell reactivity to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in significant numbers of non-infected individuals, which has been attributed to cross-reactive CD4 memory T cells from previous exposure to seasonal coronaviruses. Less evidence of cross-reactive memory CD8 T cells has been documented to date.
We used the NetCTLPan neural network of the Epitope Database and Analysis Resource to select a series of 27 HLA-A02:01 epitopes derived from the proteome of SARS-CoV-2. Their binding capacity was assessed by a HLA-A02:01 stabilization assay and by quantifying their binding to HLA-A*02:01 monomers for the generation of tetramers. Their ability to stimulate and induce expansion of SARS-CoV-2 reactive CD8 T cells was measured by flow cytometry. The TCR repertoire of COVID convalescent and healthy unexposed donors was analysed using the MIRA database.
The HLA-A*02:01 epitopes tested were able to stabilise HLA molecules and induce activation of CD8 T cells of healthy unexposed donors. Our results, based on specific tetramer binding, provide evidence supporting the presence of frequent cross-reactive CD8 T cells to SARS-CoV-2 antigens in non-exposed individuals. Interestingly, the reactive cells were distributed into naïve, memory and effector subsets.
Our data are consistent with a significant proportion of the reactive CD8 T clones belonging to the public shared repertoire, readily available in absence of previous contact with closely related coronaviruses. Furthermore, we demonstrate the immunogenic capacity of long peptides carrying T cell epitopes, which can serve to isolate virus-specific T cell receptors among the ample repertoire of healthy unexposed subjects and could have application in COVID-19 immunotherapy. Limitations of our study are that it concentrated on one MHC I allele (HLA-A*02:01) and the low numbers of samples and epitopes tested.
See the Acknowledgements section.
最近的研究表明，大量未感染的个体对严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）存在 T 细胞反应性，这归因于先前接触季节性冠状病毒而产生的交叉反应性 CD4 记忆 T 细胞。迄今为止，记录到的交叉反应性记忆 CD8 T 细胞的证据较少。
我们使用 Epitope Database and Analysis Resource 的 NetCTLPan 神经网络来选择来自 SARS-CoV-2 蛋白质组的一系列 27 个 HLA-A02:01 表位。通过 HLA-A02:01 稳定测定和量化它们与 HLA-A*02:01 单体的结合来评估它们的结合能力，以产生四聚体。通过流式细胞术测量它们刺激和诱导 SARS-CoV-2 反应性 CD8 T 细胞扩增的能力。使用 MIRA 数据库分析 COVID 恢复期和健康未暴露供体的 TCR 库。
测试的 HLA-A*02:01 表位能够稳定 HLA 分子并诱导健康未暴露供体的 CD8 T 细胞活化。我们的结果基于特定四聚体结合，提供了在未暴露个体中存在频繁交叉反应性 SARS-CoV-2 抗原的 CD8 T 细胞的证据支持。有趣的是，反应性细胞分布在幼稚、记忆和效应亚群中。
我们的数据与大量反应性 CD8 T 克隆属于公共共享库的比例一致，在没有先前接触密切相关冠状病毒的情况下，这些克隆随时可用。此外，我们证明了携带 T 细胞表位的长肽的免疫原性，这些表位可用于在健康未暴露的受试者的广泛库中分离病毒特异性 T 细胞受体，并可应用于 COVID-19 免疫治疗。我们研究的局限性在于它集中在一个 MHC I 等位基因（HLA-A*02:01）和测试的样本和表位数量较少。
见致谢部分。
