The impact of HLA-B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Epitope selection in T cell responses to persistent viruses like human cytomegalovirus (CMV) is not fully understood.
• Human leukocyte antigen (HLA) class I molecules present viral peptides to T cells, influencing immune responses.

Purpose of the Study:

• To investigate the factors controlling epitope selection in the T cell response to CMV.
• To examine the impact of HLA-B allotype variation on the immunodominance hierarchy of CMV pp65 epitopes.

Main Methods:

• Analysis of T cell responses to four HLA-B*35-binding peptides from the CMV pp65 antigen in healthy individuals.
• Comparison of peptide-MHC (major histocompatibility complex) association and dissociation rates with peptide immunogenicity.
• Genotyping of HLA-B*3501 and HLA-B*3508 allotypes.

Main Results:

• Significant differences in epitope immunodominance hierarchy were observed between HLA-B*3501 and HLA-B*3508 allotype carriers.
• HLA-B*3501(+) individuals responded strongly to specific pp65 epitopes, while HLA-B*3508(+) individuals preferred different epitopes.
• Peptide dissociation rates from MHC molecules correlated more closely with the observed immunodominance hierarchy.

Conclusions:

• Micropolymorphism in HLA molecules, even at positions outside primary binding pockets, critically affects T cell determinant selection in antiviral responses.
• These findings highlight the role of HLA diversity in shaping immune responses to persistent viral infections and may explain the maintenance of related HLA molecules in human populations.