title: The impact of HLA-B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV.
abstract: The factors controlling epitope selection in the T cell response to persistent viruses are not fully understood, and we have examined this issue in the context of four HLA-B*35-binding peptides from the pp65 antigen of human cytomegalovirus, two of which are previously undescribed. Striking differences in the hierarchy of immunodominance between these four epitopes were observed in healthy virus carriers expressing HLA-B*3501 versus B*3508, two HLA-B allotypes that differ by a single amino acid at position 156 (HLA-B*3501, (156)Leucine; HLA-B*3508, (156)Arginine) that projects from the alpha2 helix into the centre of the peptide-binding groove. While HLA-B*3501(+) individuals responded most strongly to the (123)IPSINVHHY(131) and (366)HPTFTSQY(373) epitopes, HLA-B*3508(+) individuals responded preferentially to (103)CPSQEPMSIYVY(114) and (188)FPTKDVAL(195). By comparing peptide-MHC association and disassociation rates with peptide immunogenicity, it was clear that dissociation rates correlate more closely with the hierarchy of immunodominance among the four pp65 peptides. These findings demonstrate that MHC micropolymorphism at positions outside the primary anchor residue binding pockets can have a major impact on determinant selection in antiviral T cell responses. Such influences may provide the evolutionary pressure that maintains closely related MHC molecules in diverse human populations.
authors.affiliation: Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, Brisbane, Australia. scott.burrows@qimr.edu.au
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Burrows
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Wynn
authors.forename: Fleur E
authors.initials: FE
authors.lastname: Tynan
authors.forename: Julia
authors.initials: J
authors.lastname: Archbold
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Bell
authors.forename: Rebekah M
authors.initials: RM
authors.lastname: Brennan
authors.forename: Susan
authors.initials: S
authors.lastname: Walker
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Rajiv
authors.initials: R
authors.lastname: Khanna
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001665:Binding Sites; D003587:Cytomegalovirus / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015235:HLA-B Antigens / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D011110:Polymorphism, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D010455:Peptides