Unconventional CD8⁺ T cell surveillance of cytomegalovirus via Qa-1/HLA-E-restricted epitope recognition

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• Nonclassical CD8+ T cells can compensate for classical CD8+ T cell responses during cytomegalovirus infection.
• The role of Qa-1 and HLA-E restricted T cells in viral immunity is not fully understood.

Purpose of the Study:

• Identify viral peptides binding to Qa-1 and HLA-E.
• Investigate the function of Qa-1/HLA-E restricted CD8+ T cells in cytomegalovirus infection.
• Explore therapeutic potential for vaccine development.

Main Methods:

• Motif-based discovery, predictive algorithms, and AlphaFold3 structural modeling.
• Biological assays, including tetramer staining and adoptive T cell transfer.
• Single-cell RNA/TotalSeq and single-cell T cell receptor sequencing.

Main Results:

• Identified MCMV and HCMV peptides binding to Qa-1 and HLA-E, respectively.
• Demonstrated stimulation of Qa-1-restricted CD8+ T cells by viral antigens.
• Showed adoptive transfer of these T cells protects against mortality in RAG-1 deficient mice.
• Revealed expansion of unique TCR clonotypes indicating convergent antigen specificity.

Conclusions:

• Uncovered a conserved, functionally important nonclassical CD8+ T cell axis mediated by Qa-1/HLA-E.
• This axis modulates adaptive immunity independently of classical MHC-I pathways.
• Identified novel opportunities for vaccine development targeting cytomegalovirus.