Major histocompatibility complex (MHC) class I and II peptide-binding grooves presenting SARS-CoV-2-derived epitopes (pMHC-SARS-CoV-2)

The MHC class I and II peptide-binding grooves presenting SARS-CoV-2-derived epitopes constitute the primary molecular targets for the adaptive cellular immune response against COVID-19 (Shomuradova et al., 2020). MHC class I molecules (HLA-A, -B, -C) present short peptides derived from intracellular viral proteins to CD8+ cytotoxic T cells, while MHC class II molecules (HLA-DR, -DQ, -DP) present longer peptides to CD4+ helper T cells (Nguyen et al., 2020). These complexes are formed when viral proteins, such as the Spike, Nucleocapsid, or Membrane proteins, are proteolytically processed by the host cell's pathways and loaded into the MHC binding grooves (Rammensee et al., 2021). The resulting peptide-MHC (pMHC) complexes are then displayed on the cell surface for recognition by specific T-cell receptors (TCRs). Therapeutically, these complexes are the intended end-products of COVID-19 vaccines, including mRNA and viral vector platforms, which provide the genetic instructions for the host to produce and present these viral antigens (Borbulevych et al., 2005). Beyond vaccines, these pMHC complexes are being explored as targets for next-generation immunotherapies, such as TCR-mimic antibodies and TCR-engineered T cells, which can specifically identify and eliminate infected cells (Augsberger et al., 2021). A significant challenge in targeting these complexes is HLA restriction, as the specific peptides presented depend on an individual's highly polymorphic HLA genotype (Khan et al., 2020). Additionally, the potential for molecular mimicry between viral epitopes and self-antigens remains a safety consideration in the design of these therapies (Rojas et al., 2018). Furthermore, mutations in the viral genome can lead to immune escape by altering the binding affinity of epitopes for the MHC groove or preventing TCR recognition (Obermair et al., 2022).

Other names

HLA-SARS-CoV-2 peptide complexSARS-CoV-2 T-cell epitopesHLA-restricted SARS-CoV-2 epitopespMHC-SARS-CoV-2 complexMajor histocompatibility complex-peptide complex

Vaccines induce the intracellular production and subsequent presentation of SARS-CoV-2 peptides within MHC grooves to activate T-cell mediated immunity; experimental TCR-mimic antibodies and TCR-T cells directly bind these complexes to eliminate infected cells.