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 Epitopes

摘要

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 (HLAnat) (with human β2-microglobulin) and as hybrid human/mouse (HLAhyb) molecules on the H2b background. To eliminate the influence of H2b class I, each HLA Tg strain was bred with a H2-Kb/H2-Db-double knockout (DKO) strain to generate mice in which the only classical class I expression was the human molecule. Expression of each HLAhyb molecule and HLA-B27nat/human β2-microglobulin led to peripheral CD8+ T cell levels comparable with that for mice expressing a single H2-Kb or H2-Db gene. Influenza A infection of Tg HLA-B27hyb/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-B7hyb/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.