HLA-B*0702 transgenic, H-2KbDb double-knockout mice: phenotypical and functional characterization in response to influenza virus.
HLA-B*0702 transgenic mice (expressing a chimeric heavy chain with a murine alpha 3 domain: HLA-B7(m alpha 3)) in which the H-2K(b) and H-2D(b) class I-a (Cl I-a(-/-)) genes have been inactivated were compared with H-2K(b)D(b) Cl I-a(+/+) positive controls. Expression of the HLA-B7(m alpha 3) molecules resulted in a 3- to 4-fold increase in peripheral CD8(+) T lymphocyte numbers compared to H-2 Cl 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-B7(m alpha 3), H-2 Cl I-a(-/-) compared to HLA-B7(m alpha 3), H-2 Cl I-a(+/+) mice. The CTL response of infected HLA-B7(m alpha 3), H-2 Cl 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 HLA-B0702-restricted CTL responses.
Hôpital Robert Debré, and Unité d'Immunité Cellulaire Antivirale, Département d'Immunologie, Institut Pasteur, Paris, France.
Pierre-Simon
PS
Rohrlich
Sylvain
S
Cardinaud
Hüseyin
H
Firat
Mustapha
M
Lamari
Pascale
P
Briand
Nicolas
N
Escriou
François A
FA
Lemonnier
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006183:H-2 Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D015793:HLA-B7 Antigen; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology; D009975:Orthomyxoviridae / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; C032876:H-2Kb protein, mouse; D015235:HLA-B Antigens; C477444:HLA-B*07:02 antigen; D015793:HLA-B7 Antigen; D009698:Nucleoproteins; D011948:Receptors, Antigen, T-Cell