T lymphocyte activation is driven by the recognition of Human Leukocyte Antigens (HLA) on the surface of infected cells. HLAs present viral peptides to T cells, which are then recognize as antigens via the T cell receptor (TCR). Our previous work (1.) showed that a specific HLA- B15:01 can present both a SARS-CoV-2 peptide (NQK-Q8) and a Seasonal Coronavirus peptide (NQK-A8) in the same conformation, with the same thermal stability. We also demonstrated that these peptides elicit a similar T-cell response, driven by high-affinity binding of identical TCRs found in different HLA-B15:01+ individuals.
To further investigate these results, I used X-ray crystallography to show that these public TCRs contact two residues on NQK-Q8 and NQK-A8, with half of the TCR interaction involving the HLA alone. To prove how vital these peptide residues are to TCR recognition, I solved the crystal structures, thermal stability, and binding affinity of HLA-B*15:01 presenting homologous NQK peptides containing different mutations. I found that even a single residue mutation can cause substantial changes in peptide conformation. This can reduce overall complex stability, limit binding affinity, and decrease CD8+ T cell stimulation.
My work shows that CD8+ T cell activation in HLA-B*15:01+ individuals after SARS-CoV- 2 infection is driven by unique TCR interactions. It also highlights the important role that NQK peptide side chains play in this process.