The molecular mechanisms of CD8+ T cell responses to SARS-CoV-2 infection mediated by TCR-pMHC interactions

Abstract

Cytotoxic CD8⁺ T lymphocytes (CTLs) have been implicated in the severity of COVID-19. The TCR-pMHC ternary complex, formed by the T cell receptor (TCR) and peptide-MHC (major histocompatibility complex), constitutes the molecular basis of CTL responses against SARS-CoV-2. While numerous studies have been conducted on T cell immunity, the molecular mechanisms underlying CTL-mediated immunity against SARS-CoV-2 infection have not been well elaborated. In this review, we described the association between HLA variants and different immune responses to SARS-CoV-2 infection, which may lead to varying COVID-19 outcomes. We also summarized the specific TCR repertoires triggered by certain SARS-CoV-2 CTL epitopes, which might explain the variations in disease outcomes among different patients. Importantly, we have highlighted the primary strategies used by SARS-CoV-2 variants to evade T-cell killing: disrupting peptide-MHC binding, TCR recognition, and antigen processing. This review provides valuable insights into the molecule mechanism of CTL responses during SARS-CoV-2 infection, aiding efforts to control the pandemic and prepare for future challenges.

Keywords: HLA; SARS-CoV-2; TCR repertoire; TCR-pHLA; TCR-pMHC; cytotoxic T lymphocytes (CTL); epitope; mutations.

Figure 1

The identification of immunodominant antigenic regions of SARS-CoV-2 CTL epitopes. (A-E) CTL Epitope assay counts of five viral proteins (ORF1ab, Spike, N, M, and ORF3a) were analyzed using the IEDB’s Immunome Browser tool to identify potential antigenic regions. The number of positive and negative assays are indicated for each residue position.

Figure 2

Overview of CTL response to SARS-CoV-2 infection mediated by TCR-pMHC complex. (A) Antigen presenting cells (APCs) endocytose SARS-CoV-2 and degrade it through antigen processing. These epitope fragments are then presented on the cell surface by MHC molecules and allow recognition by T cells. TCR genes of the α-chain (TCRα) and β-chain (TCRβ) on the T cell surface are recombined to produce a diverse TCR repertoire. If a CD8⁺ T cell is able to bind pMHC, it will undergo clonal expansion and directly target infected cells through perforin/granase, FAS ligand/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, or secretion of pro-inflammatory mediators. CDR1 and CDR2 are encoded by TRBAV and TRABV genes, and CDR3 encompasses VJ regions (for TCRα) or VDJ regions (for TCRβ). Non-template nucleotide insertions and deletions are represented by black boxes. MHC-α (green), β2m (sand), Peptide (magenta), TCRα (teal), TCRβ (salmon), TCRα-CDR1 (red), TCRα-CDR2 (orange), TCRα-CDR3 (yellow), TCRβ-CDR1 (blue), TCRβ-CDR2 (green), TCRβ-CDR3 (maroon). (B–E) Histograms of V gene usage across the sequences of YLQ-, NYN-, PTD-, LLY-specific TCRs. Only the top ten of each gene are shown.

Figure 3

The structural basis of SPR, NQK, and QYI peptides for selective T cell cross-reactivity. (A) Peptide homologs of other HCoVs compared to the SARS-CoV-2 SPR peptide. (B) Structural superposition of the SPR-HLA-B7 (ID 7LGD) and SPK-HLA-B7 (ID 7LGT). SPR peptide (magenta), SPK peptide (cyan), HLA-B7 (grey). (C) Top view of the SPR-HLA-B7 and SPK-HLA-B7, with stick representation of the SPR and SPK peptides. Blue and black dashed lines indicate intra-peptide interactions of the SPR and SPK peptide, respectively. (D) Peptide homologs of other HCoVs compared to the SARS-CoV-2 NQK peptide. (E) Structural superposition of the NQK-HLA-B15 (ID 8ELH) and NQK-A8-HLA-B15 (ID 8ELG). NQK peptide (magenta), NQK-A8 peptide (cyan), HLA-B15 (grey). (F) Top view of the SPR-HLA-B7 and SPK-HLA-B7, with stick representation of the SPR and SPK peptides. (G) Peptide homologs of other HCoVs compared to the SARS-CoV-2 QYI peptide. (H) Structural superposition of the QYI-HLA-A24 (ID 7EJL), TYI-HLA-A24 (ID 7EJM), and MYV-HLA-A24 (ID 7EJN). QYI peptide (magenta), TYI peptide (cyan), MYV peptide (purple blue), HLA-A24 (grey). (I) Top view of the QYI-HLA-A24, TYI-HLA-A24, and MYV-HLA-A24, with stick representations of the QYI, TYI and MYV peptides.

Figure 4

Schematic view of the TCR-pMHC I ternary complex. (A, B) Side view of YLQ7-YLQ-HLA-A2 (ID 7N1F). MHC-α (grey), β2m (sand), YLQPRTFLL-peptide (magenta), TCRα (teal), TCRβ (salmon), CDR1α (red), CDR2α (orange), CDR3α (yellow), CDR1β (light pink), CDR2β (light blue), CDR3β (green). (C) Footprint of TCR YLQ7 on YLQ-HLA-A2. (D) Cartoon comparison of eight TCR-pMHC ternary complexes presenting SARS-CoV-2 CD8⁺ T cell epitopes, including YLQ7-YLQ-HLA-A2 (ID 7N1F, cyan), YLQ36-YLQ-HLA-A2 (ID 7PBE, slate), NR1C-YLQ-HLA-A2 (ID 7N6E, magenta), SG3-YLQ-HLA-A2 (ID 7RTR, sand), RLQ3-RLQ-HLA-A2 (ID 7N1E, green), RLQ7-RLQ-HLA-A2 (ID 8GOM, salmon), RLQ7-RLQ-T1006I-HLA-A2 (ID 8GON, grey), TCR^NYN-I-NYN-HLA-A24 (ID 8YE4, light pink).

Figure 5

Mechanism of CTL immune evasion mediated by SARS-CoV-2 epitope mutation. (A) Comparison of YLQ-HLA-A2 (ID 7P3D) and YLQ-P272L-HLA-A2 (ID 7P3E). Intrapeptide bonds present in YLQ-HLA-A2 are shown as blue dashes. YLQ peptide (grey sticks), YLQ-P272L peptide (cyan sticks), HLA-A2 (grey cartoon). (B) Comparison of unbound YLQ-HLA-A2 (ID 7P3D) and TCR-bound YLQ-HLA-A2 (ID 7PBE) peptide presentation. Intrapeptide bonds present in TCR-unbound and TCR-bound YLQ-HLA-A2 are shown as blue and black dashes, respectively. TCR-bound YLQ peptide (magenta), TCR-unbound YLQ peptide (grey sticks), HLA-A2 (grey cartoon). (C) YLQ and YLQ-P272L P4 residues shown as magenta and grey sticks, respectively. YLQ36 CDR3α loop shown as yellow sticks. (D) Comparison of NYN-HLA-A24 (ID 7F4W) and NYN-Y453F-HLA-A24 (ID 8ZV9). NYN peptide (magenta), NYN-Y453F peptide (cyan), HLA-A24 (grey). (E) Comparison of unbound NYN-HLA-A24 (ID 7F4W) and TCR-bound TCR^NYN-I-NYN-HLA-A24 (ID 8YE4) peptide presentation. The van der Waals and hydrogen bonds between P6-Tyr and TCR^NYN are blue and black dashes, respectively. (F) NYNYLYRLF and NYNYLFRLF P6 residues shown as magenta and cyan sticks, respectively. HLA-A24 shown as grey cartoon. TCRNYN-I CDR1α, CDR3α and CDR3β loops shown as red, yellow and green sticks, respectively. Hydrogen bonds are shown in black dashes. Van der Waals contacts are shown as blue dashes. (G) Structural rearrangements in RLQ-HLAs resulting from the T1006I mutation. RLQ-HLA-A2 (TCR RLQ7-HLA-A2, ID 8GOM), RLQ-T1006I-HLA-A2 (TCR RLQ7-T1006I-HLA-A2, ID 8GON), RLQ peptide (magenta), RLQ-T1006I peptide (cyan), HLA-A2 (grey). (H) Interactions between CDR1α of RLQ7 (red) and the RLQ peptide (magenta). Yellow sphere indicates an interfacial water molecule. Water-mediated hydrogen bonds are yellow dashed lines. Hydrogen bonds are black dashed lines. (I) Interactions between CDR1α of RLQ7 (red) and the RLQ-T1006I peptide (cyan). Hydrogen bonds are represented by black dashed.