CD8+ T-cell immune escape by SARS-CoV-2 variants of concern

Abstract

Despite the efficacy of antiviral drug repositioning, convalescent plasma (CP), and the currently available vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the worldwide coronavirus disease 2019 (COVID-19) pandemic is still challenging because of the ongoing emergence of certain new SARS-CoV-2 strains known as variants of concern (VOCs). Mutations occurring within the viral genome, characterized by these new emerging VOCs, confer on them the ability to efficiently resist and escape natural and vaccine-induced humoral and cellular immune responses. Consequently, these VOCs have enhanced infectivity, increasing their stable spread in a given population with an important fatality rate. While the humoral immune escape process is well documented, the evasion mechanisms of VOCs from cellular immunity are not well elaborated. In this review, we discussed how SARS-CoV-2 VOCs adapt inside host cells and escape anti-COVID-19 cellular immunity, focusing on the effect of specific SARS-CoV-2 mutations in hampering the activation of CD8⁺ T-cell immunity.

Keywords: CD8 + T-cell epitope; HLA; SARS-CoV-2; cellular immunity; cytotoxic T lymphocytes (CTL); immune escape; protein mutation; variant of concern (VOC).

Figure 1

SARS-CoV-2 impairs antigen presentation by MHC-I to CD8+ T cells through ORF8. Once entered into the epithelial cells by endocytosis, the genomic RNA is released. SARS-CoV-2 uses the cell protein expression machinery to synthesize the viral proteins. The antigen processing and presentation pathways occur for viral protein lysis into peptides. Simultaneously, the MHC-I will mature in the ER and migrate to the Golgi apparatus, where peptides will be loaded onto MHC-I molecules and presented to CD8⁺ cytotoxic T lymphocytes (CTLs), activating the cell cytotoxic response (A). When infected with SARS-CoV-2, especially variants of concern, the viral proteins, including the ORF8, are produced inside ER-derived DMVs containing LC3-I. The synthesized ORF8 protein directly interacts with the MHC-I and leads MHC-I trafficking from ER to autophagosome vesicles, inducing the early stages of autophagy and accumulation of autophagosomes thanks to beclin 1-activated upregulation. The matured autophagosome then fuses with the lysosome to form the autolysosome, inside which MHC-I is digested by lysozymes. This results in the loss of sensitivity of SARS-CoV-2–infected cells to CD8⁺ T cells and lysis by CTLs. When infection occurs with VOCs, the mechanism is strongly enhanced, and the SARS-CoV-2 variant easily escapes T cells (B). ER, endoplasmic reticulum; DMV, doubled membrane vesicle; LC3-I, microtubule-associated protein 1A/1B-light chain 3B; MHC-I, major histocompatibility complex type I.

Figure 2

Molecular bases of epitope–HLA-I complexes and effects of epitope mutations. Interactions between KIA_S peptide and HLA-A*02:01 (from PDB:7EU2) (A), NYN_S peptide and HLA-A*24:02 (7F4W) (B), RLQ peptide and HLA-A*02:01 (7N1B) (C), and YLQ peptide and HLA-A*02:01 (7N1A) (D). For all the structures, HLA heavy chains are green, the SARS-CoV-2 peptides are purple, and residues with predominant mutational rates with an effect on immune escape are shown in yellow. Residues at the interface of the interaction of HLA with peptides are represented: nitrogen atoms in blue, oxygen atoms in red, and hydrogen bonds are indicated by black dashed lines.

Figure 3

Molecular bases of TCR–epitope–HLA-I complexes and effects of epitope mutations. (A) Overview of RLQ3–RLQ–HLA-A2 complex (7N1E). (B) Close-up view of interactions of T1006 (yellow), residue with predominant mutational rates in VOCs, with TCR RLQ3 and HLA-A2. (C) Overview of YLQ7–YLQ–HLA-A2 complex (7N1F). (D, E) Close-up view of interactions of T274 and L270 (yellow), with TCR YLQ7 and HLA-A2. For all the structures, HLA heavy chains are green, the SARS-CoV-2 peptides are purple, while residues with a predominant mutational rate with an effect on immune escape are shown in yellow. Residues at the interface of the interaction of HLA with peptides are represented: nitrogen atoms in blue, oxygen atoms in red, and hydrogen bonds are indicated by black dashed lines.

Figure 4

SARS-CoV-2 S protein mutations prevent cellular immunity activation. Once entered into the target cell, SARS-CoV-2 releases its genomic RNA, which serves to produce the viral proteins, including structural and nonstructural proteins. Recognized as non-self-molecules, antigen processing and presentation pathways occur for viral protein lysis into peptides that are then loaded onto the MHC-I or HLA molecules and presented to CD8⁺ CTLs, activating the cell cytotoxic response. The CD8⁺ T cells produce numerous toxic substances (perforins, granzyme, and FasL) and cytokines (IFN-γ, TNF-α, and IL-2) directly involved in SARS-CoV-2–infected cell death (A) (30, 32). However, because of the mutations in specific antigen peptides (such as spike-mutated derived antigens), these later lose their binding affinity to HLA-I. Consequently, the peptides are either not loaded or unstably loaded onto the corresponding HLA molecules. This leads to the reduction or non-activation of the CD8⁺ T cells through low affinity or absence of HLA-I-peptide recognition by TCR, resulting in cellular immune escape and infection maintenance by SARS-CoV-2 variants (B). MHC-I, major histocompatibility complex type I; CTL, cytotoxic T lymphocyte.