Impaired and restored CD8+ T cell responses to a sequentially mutated spike epitope in Omicron variants

TL;DR

The study examines how mutations in the spike protein of Omicron variants affect CD8+ T cell responses and identifies a key epitope involved in immune evasion.

Contribution

The study identifies a specific CD8+ T cell epitope (LYN) that is affected by mutations in Omicron variants and contributes to immune evasion.

Findings

BA.2 mutations more profoundly attenuate LYN-specific cellular immunity compared to BA.1 mutations.

T376A mutation is a major contributor to immune evasion as shown by structural analysis.

Breakthrough infection mitigates the immune evasion effect and the LYN sequence remains conserved in the NB.1.8.1 lineage.

Abstract

In the post-pandemic era, SARS-CoV-2 variants continue to circulate and evolve. T cell-mediated immunity is essential for antiviral defense, but its evasion by emerging variants remains poorly defined. In this study, we screened spike-derived CD8+ T cell epitopes using bioinformatic algorithms and validated them experimentally in COVID-19 vaccine recipients. LYNSASFSTF (LYN), located in the receptor-binding domain (S368–377), was identified as an HLA-A*24:02-restricted epitope harboring mutations observed in Omicron BA.1 (S371L, S373P, and S375F) and BA.2 (S371F, S373P, S375F, and T376A). BA.2 mutations more profoundly attenuated LYN-specific cellular immunity than those from BA.1 with T376A as a major contributor to immune evasion, as supported by structural analysis of altered peptide–HLA interactions. This effect was mitigated by BA.1/BA.2 breakthrough infection and appears unlikely to persist in the currently dominant NB.1.8.1 lineage, where the LYN sequence remains conserved. Our findings suggest that LYN may function both as an immune-evasive hotspot and as a cross-reactive epitope, underscoring the importance of continued epitope-level surveillance as future variants emerge.

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