Relative dominance of HLA-B*07 restricted CD8+ T-lymphocyte immune responses to human cytomegalovirus pp65 in persons sharing HLA-A*02 and HLA-B*07 alleles.
CD8(+) T-cell responses to three human cytomegalovirus (CMV) pp65 epitopes were studied in panels of healthy seropositive HLA-A*02/HLA-B*07 individuals, and HLA-A*02 donors mismatched for HLA-B*07. The majority of the latter had significant responses to a HLA-A*02-restricted epitope within the CMV pp65 antigen. By contrast, the strongest responses to CMV in the first group were to HLA-B*07-restricted epitopes. Similar immunodominance of HLA-B*07 over HLA-A*02 was found in two immunocompromised HIV-infected HLA-A*02/HLA-B*07 patients, and in the reconstituting immune system of three stem cell transplant recipients. In vitro stimulation of peripheral blood mononuclear cells (PBMC) from two immunocompetent HLA-A*02/HLA-B*07 individuals indicated that cytotoxic T lymphocyte (CTL) precursors specific for both HLA-A*02 and HLA-B*07 restricted epitopes were present and could be expanded by stimulation with the cognate peptides. However, if stimulation was performed by antigen presenting cells infected with recombinant vaccinia expressing full-length native pp65, only HLA-B*07 epitope-specific cells were seen. In one patient the HLA-B*07 dominance was partially broken by using recombinant vaccinia expressing ubiquitinated pp65, suggesting that enhanced protein processing can reveal weaker immune responses. Our results indicate that CMV-specific cellular immune responses restricted by HLA-B*07 dominate those restricted by HLA-A*02 in both immunocompetent and immunocompromised individuals. This may have significant consequences for the design of epitope-specific vaccines.
Lacey
Simon F
SF
Laboratory of Vaccine Research, Division of Virology, Beckman Institute of the City of Hope, City of Hope Medical Centre, Duarte, CA 91010, USA. slacey@coh.org
Villacres
Maria C
MC
La Rosa
Corinna
C
Wang
Zhongde
Z
Longmate
Jeff
J
Martinez
Joybelle
J
Brewer
John C
JC
Mekhoubad
Shahram
S
Maas
Rebecca
R
Leedom
John M
JM
Forman
Stephen J
SJ
Zaia
John A
JA
Diamond
Don J
DJ
D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics*; D015235:HLA-B Antigens / Q000235:genetics*; D015793:HLA-B7 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D010446:Peptide Fragments / Q000494:pharmacology; D010750:Phosphoproteins / Q000276:immunology*; D033581:Stem Cell Transplantation; D014763:Viral Matrix Proteins / Q000276:immunology*
D016207:Cytokines; D015234:HLA-A Antigens; D015235:HLA-B Antigens; C425023:HLA-B*07 antigen; D015793:HLA-B7 Antigen; D016056:Immunodominant Epitopes; D007376:Interleukin-2; D010446:Peptide Fragments; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa