A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses.

IF 4.1 Q2 IMMUNOLOGY Immunotherapy advances Pub Date : 2023-03-15 eCollection Date: 2023-01-01 DOI:10.1093/immadv/ltad005
Paul R Buckley, Chloe H Lee, Agne Antanaviciute, Alison Simmons, Hashem Koohy
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Abstract

T cell recognition of SARS-CoV-2 antigens after vaccination and/or natural infection has played a central role in resolving SARS-CoV-2 infections and generating adaptive immune memory. However, the clinical impact of SARS-CoV-2-specific T cell responses is variable and the mechanisms underlying T cell interaction with target antigens are not fully understood. This is especially true given the virus' rapid evolution, which leads to new variants with immune escape capacity. In this study, we used the Omicron variant as a model organism and took a systems approach to evaluate the impact of mutations on CD8+ T cell immunogenicity. We computed an immunogenicity potential score for each SARS-CoV-2 peptide antigen from the ancestral strain and Omicron, capturing both antigen presentation and T cell recognition probabilities. By comparing ancestral vs. Omicron immunogenicity scores, we reveal a divergent and heterogeneous landscape of impact for CD8+ T cell recognition of mutated targets in Omicron variants. While T cell recognition of Omicron peptides is broadly preserved, we observed mutated peptides with deteriorated immunogenicity that may assist breakthrough infection in some individuals. We then combined our scoring scheme with an in silico mutagenesis, to characterise the position- and residue-specific theoretical mutational impact on immunogenicity. While we predict many escape trajectories from the theoretical landscape of substitutions, our study suggests that Omicron mutations in T cell epitopes did not develop under cell-mediated pressure. Our study provides a generalisable platform for fostering a deeper understanding of existing and novel variant impact on antigen-specific vaccine- and/or infection-induced T cell immunity.

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评估严重急性呼吸系统综合征冠状病毒2型变异株相关突变对CD8+T细胞反应影响的系统方法。
接种疫苗和/或自然感染后,T细胞对严重急性呼吸系统综合征冠状病毒2型抗原的识别在解决严重急性呼吸系综合征病毒2型感染和产生适应性免疫记忆方面发挥了核心作用。然而,严重急性呼吸系统综合征冠状病毒2型特异性T细胞反应的临床影响是可变的,T细胞与靶抗原相互作用的机制尚不完全清楚。考虑到病毒的快速进化,这一点尤其正确,这会导致具有免疫逃逸能力的新变种。在这项研究中,我们使用奥密克戎变异株作为模型生物,并采用系统方法评估突变对CD8+T细胞免疫原性的影响。我们计算了来自祖先毒株和奥密克戎的每种严重急性呼吸系统综合征冠状病毒2肽抗原的免疫原性潜在评分,捕捉了抗原呈递和T细胞识别概率。通过比较祖先与奥密克戎的免疫原性评分,我们揭示了CD8+T细胞识别奥密克戎变异株中突变靶点的影响存在差异和异质性。虽然T细胞对奥密克戎肽的识别被广泛保留,但我们观察到免疫原性恶化的突变肽可能有助于某些个体的突破性感染。然后,我们将我们的评分方案与计算机诱变相结合,以表征位置和残基特异性理论突变对免疫原性的影响。虽然我们从取代的理论前景中预测了许多逃逸轨迹,但我们的研究表明,T细胞表位中的奥密克戎突变并不是在细胞介导的压力下产生的。我们的研究提供了一个通用的平台,有助于更深入地了解现有和新的变体对抗原特异性疫苗和/或感染诱导的T细胞免疫的影响。
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审稿时长
7 weeks
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