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Human MHC Class I Transgenic Mice Deficient for H2 Class I Expression Facilitate Identification and Characterization of New HLA Class I-Restricted Viral T Cell Epitopes¹

Eve Cheuk^*,, Celine D’Souza^*, Ningjie Hu^*, Youan Liu^*, Haili Lang^* and John W. Chamberlain^2,*,,

^* Research Institute, Program in Infection, Immunity, Injury and Repair, The Hospital for Sick Children, Toronto, Canada; and Department of Immunology and Institute of Medical Science, University of Toronto, Toronto, Canada

Although mice transgenic (Tg) for human MHC (HLA) class I alleles could provide an important model for characterizing HLA-restricted viral and tumor Ag CTL epitopes, the extent to which Tg mouse T cells become HLA restricted in the presence of endogenous H2 class I and recognize the same peptides as in HLA allele-matched humans is not clear. We previously described Tg mice carrying the HLA-B27, HLA-B7, or HLA-A2 alleles expressed as fully native (HLA^nat) (with human ₂-microglobulin) and as hybrid human/mouse (HLA^hyb) molecules on the H2^b background. To eliminate the influence of H2^b class I, each HLA Tg strain was bred with a H2-K^b/H2-D^b-double knockout (DKO) strain to generate mice in which the only classical class I expression was the human molecule. Expression of each HLA^hyb molecule and HLA-B27^nat/human ₂-microglobulin led to peripheral CD8⁺ T cell levels comparable with that for mice expressing a single H2-K^b or H2-D^b gene. Influenza A infection of Tg HLA-B27^hyb/DKO generated a strong CD8⁺ T cell response directed at the same peptide (flu nucleoprotein NP383–391) recognized by CTLs from flu-infected B27⁺ humans. As HLA-B7/flu epitopes were not known from human studies, we used flu-infected Tg HLA-B7^hyb/DKO mice to examine the CTL response to candidate peptides identified based on the B7 binding motif. We have identified flu NP418–426 as a major HLA-B7-restricted flu CTL epitope. In summary, the HLA class I Tg/H2-K/H2-D DKO mouse model described in this study provides a sensitive and specific approach for identifying and characterizing HLA-restricted CTL epitopes for a variety of human disease-associated Ags.

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