Cross-reactive and mono-reactive SARS-CoV-2 CD4+ T cells in prepandemic and COVID-19 convalescent individuals.
Cross-reactive and mono-reactive SARS-CoV-2 CD4+ T cells in prepandemic and COVID-19 convalescent individuals.
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DOI：
10.1371/journal.ppat.1010203
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发表时间：
2021-12
期刊：
影响因子：
6.7
通讯作者：
Kwok WW
中科院分区：
文献类型：
--
作者：
Johansson AM;Malhotra U;Kim YG;Gomez R;Krist MP;Wald A;Koelle DM;Kwok WW
II类四聚体试剂的11个常见的DR等位基因和DP等位基因流行的世界人口被用来确定SARS-CoV-2的CD 4 + T细胞表位。共鉴定了112个、28个和42个分别对刺突、膜和核衣壳具有特异性的表位，具有确定的HLA限制性。使用四聚体试剂直接离体染色PBMC来确定免疫显性和亚显性T细胞表位，并估计这些T细胞在SARS-CoV-2暴露和未暴露个体中的频率。大多数SARS-CoV-2表位与地方性冠状病毒具有<67%的氨基酸序列同一性，并且不太可能引起高亲和力交叉反应性T细胞应答。鉴定了4个SARS-CoV-2刺突反应表位，包括DPB 1 *04：01限制性表位，与地方性冠状病毒具有≥67%的氨基酸序列同一性。针对这些表位中的三个的SARS-CoV-2 T细胞系引起了对地方性感冒病毒的交叉反应性T细胞应答。一种地方性冠状病毒刺突T细胞系对第四个SARS-CoV-2表位表现出交叉反应性。刺突交叉反应性表位中的三个是亚显性表位，而DPB 1 *04：01限制性表位是显性表位。频率分析显示，四聚体检测到的刺突交叉反应性T细胞在未暴露人群中的频率相对较低，仅占COVID-19恢复期个体总体刺突特异性CD 4 + T细胞的一小部分。总之，这些结果表明，如通过四聚体检测到的非常有限数量的SARS-CoV-2 T细胞能够以相对高的亲合力识别ccCoV，反之亦然。这些高亲和力交叉反应性T细胞在抗SARS-CoV-2保护性免疫中的潜在支持作用需要进一步研究。以前的研究与激活诱导标记物检测在监测抗原特异性CD 4 + T细胞已经表明，普通感冒冠状病毒T细胞可以与SARS-CoV-2抗原交叉反应，这些交叉反应性T细胞存在于高达60%的未暴露人群。在本研究中，使用装载肽的MHC-II四聚体，使用刺突蛋白、膜蛋白和核衣壳蛋白的重叠肽组来鉴定SARS-CoV-2恢复期样品中11个HLA-DR和1个HLA-DP等位基因的表位。使用这些离体四聚体，在恢复期和大流行前样品中估计这些表位特异性T细胞的频率。基于这些频率，表位被分层为免疫显性和亚显性表位。将所鉴定的表位氨基酸序列与4种常见感冒冠状病毒进行比较。潜在的交叉反应表位被定义为普通感冒病毒和SARS-CoV-2之间具有≥67%的序列同一性。鉴定了四个潜在的刺突特异性交叉反应性表位，并证明了功能性交叉反应性。四个交叉反应性表位确定，三个亚显性表位引起相对较低的频率在未暴露和恢复期的主题。与活化诱导标记物测定的结果相反，目前的数据表明，只有有限数量的高亲合力SARS-CoV-2 T细胞（如通过四聚体检测到的）具有交叉反应性。
Class II tetramer reagents for eleven common DR alleles and a DP allele prevalent in the world population were used to identify SARS-CoV-2 CD4+ T cell epitopes. A total of 112, 28 and 42 epitopes specific for Spike, Membrane and Nucleocapsid, respectively, with defined HLA-restriction were identified. Direct ex vivo staining of PBMC with tetramer reagents was used to define immunodominant and subdominant T cell epitopes and estimate the frequencies of these T cells in SARS-CoV-2 exposed and naïve individuals. Majority of SARS-CoV-2 epitopes identified have <67% amino acid sequence identity with endemic coronaviruses and are unlikely to elicit high avidity cross-reactive T cell responses. Four SARS-CoV-2 Spike reactive epitopes, including a DPB1*04:01 restricted epitope, with ≥67% amino acid sequence identity to endemic coronavirus were identified. SARS-CoV-2 T cell lines for three of these epitopes elicited cross-reactive T cell responses to endemic cold viruses. An endemic coronavirus Spike T cell line showed cross-reactivity to the fourth SARS-CoV-2 epitope. Three of the Spike cross-reactive epitopes were subdominant epitopes, while the DPB1*04:01 restricted epitope was a dominant epitope. Frequency analyses showed Spike cross-reactive T cells as detected by tetramers were present at relatively low frequency in unexposed people and only contributed a small proportion of the overall Spike-specific CD4+ T cells in COVID-19 convalescent individuals. In total, these results suggested a very limited number of SARS-CoV-2 T cells as detected by tetramers are capable of recognizing ccCoV with relative high avidity and vice versa. The potentially supportive role of these high avidity cross-reactive T cells in protective immunity against SARS-CoV-2 needs further studies. Previous studies with activation induced marker assays in monitoring antigen-specific CD4+ T cells have shown that common cold coronavirus T cells can cross-react with SARS-CoV-2 antigens and these cross-reactive T cells are present in up to 60% of the unexposed population. In this current study, sets of overlapping peptides for Spike, Membrane, and Nucleocapsid proteins were used to identify epitopes across 11 HLA-DR and 1 HLA-DP alleles in SARS-CoV-2 convalescent samples using peptide-loaded MHC-II tetramers. Using these tetramers ex vivo, frequencies of these epitope-specific T cells were estimated in convalescent and pre-pandemic samples. Based on these frequencies, epitopes were stratified into immunodominant and subdominant epitopes. Amino acid sequences of epitopes identified were compared with 4 common cold coronaviruses. Potential cross-reactive epitopes were defined as having ≥67% sequence identity between common cold viruses and SARS-CoV-2. Four potential Spike specific cross-reactive epitopes were identified and functional cross-reactivity was demonstrated. Of the four cross-reactive epitopes identified, three were subdominant epitopes eliciting relatively low frequencies in both unexposed and convalescent subjects. In contrast to the results from the activation induced marker assays, the current data suggests that only a limited number of high avidity SARS-CoV-2 T cells as detected by tetramers are cross-reactive.
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7.3
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