HLA-B*0702 transgenic, H-2KbDb double-knockout mice: Phenotypical and functional characterization in response to influenza virus

Abstract

HLA-B*0702 transgenic mice (expressing a chimeric heavy chain with a murine α3 domain: HLA-B7mα3) in which the H-2Kb and H-2Db class I-a (CI I-a-/-) genes have been inactivated were compared with H-2KbDb CI I-a+/+ positive controls. Expression of the HLA-B7mα3 molecules resulted in a 3- to 4-fold increase in peripheral CD8+ T lymphocyte numbers compared to H-2 CI I-a-/- knockout mice. These cells show a diversified TCR repertoire. Following influenza infection, a significant improvement in HLA-B0702-restricted cytotoxic T lymphocyte (CTL) responses was observed in HLA-B7mα3, H-2 CI I-a-/- compared to HLA-B7mα3, H-2 CI I-a+/+ mice. The CTL response of infected HLA-B7mα3, H-2 CI I-a-/- mice was directed against the nucleoprotein (NP) 418-426 epitope in which mutations have accumulated. Whereas all NP 418-426 variant peptides induced a CTL response, cross-reactivity to the variants was affected. These NP mutations could have been selected over time in humans for the virus to escape HLA-B0702-restricted CTL responses since a similar response was seen in humans with, as in mice, altered cross-recognition of the NP 418-426 variants. These animals may prove a suitable model to study HA-B0702-restricted CTL responses.