Highly conserved pattern of recognition of influenza A wild-type and variant CD8+ CTL epitopes in HLA-A2+ humans and transgenic HLA-A2+/H2 class I-deficient mice.
As an in vivo model for studying human MHC (HLA) class I-restricted CTL responses to viral infection, we established a series of HLA Tg mice expressing HLA-A2, -B7 or -B27 human/mouse hybrid genes on a background deficient for H2 class I (Tg HLA(hyb)/H2 class I DKO). To determine whether CTL recognition of influenza A (flu) infection in Tg HLA-A2(hyb)/H2 DKO mice is similar to HLA-A2+ humans, we compared the HLA-A2-restricted Tg mouse and human CD8+ T-cell responses to an immunodominant flu epitope (wild-type [WT] M1 58-66), as well as a variant of this peptide (var. M1 58-66). Similar to HLA-A2+ humans, our results show WT M1 58-66 is likely the dominant CTL epitope recognized in infected Tg HLA-A2(hyb)/H2 DKO mice. Var. M1 58-66 was also recognized by WT peptide-reactive T cells from both HLA-A2+ humans and Tg mice, although slightly less efficiently than WT M1 58-66 in both cases. Reduced variant recognition was shown to be associated with reduced peptide/A2 binding, as well as a more limited repertoire of utilized TCR Vbeta chains. The similar pattern of recognition and cross reaction observed here for the WT and variant M1 58-66 epitopes with HLA-A2 by human and Tg HLA mouse CTLs indicates that A2-dependent events of Ag processing, presentation and recognition are well-conserved between species. These findings demonstrate that this Tg HLA-A2/H2 DKO model will aid identification and development of epitopes as vaccines for numerous viral and tumor antigens for the HLA-A2 supertype.
Hu
Ningjie
N
Research Institute, Program in Infection, Immunity, Injury and Repair, The Hospital For Sick Children, Toronto, Ont., Canada M5G 1X8.
D'Souza
Celine
C
Cheung
Heidi
H
Lang
Haili
H
Cheuk
Eve
E
Chamberlain
John W
JW
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D000939:Epitopes / Q000276:immunology*; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007114:Immunization; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology* / Q000517:prevention & control; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000166:cytology; D022223:Vaccines, Subunit / Q000138:chemical synthesis / Q000276:immunology
D000939:Epitopes; D015789:HLA-A2 Antigen; D022223:Vaccines, Subunit; D007371:Interferon-gamma