title: Generation of a Novel HLA Class I Transgenic Mouse Model Carrying a Knock-in Mutation at the β2-Microglobulin Locus.
abstract: We generated a series of monochain HLA class I knock-in (KI) mouse strains, in which a chimeric HLA class I molecule (α1/α2 domain of HLA-A*0201, HLA-A*0301, HLA-A*2402, or HLA-A*3101 and α3 domain of H-2Db) was covalently linked with 15 aa to human β2-microglobulin (β2m) and introduced into the endogenous mouse β2m locus. In homozygous KI mice, mouse β2m gene disruption resulted in loss of the endogenous H-2 class I molecules and reduction in the peripheral CD8+T cell population that was partially restored by monochain HLA class I expression. A gene dosage-dependent expression of HLA, similar to that in human PBMCs, was detected in heterozygous and homozygous HLA KI mice. Upon vaccination with various virus epitopes, HLA-restricted, epitope-specific CTLs were induced in HLA KI mice, similar to the response in the commonly used HLA transgenic mice. Importantly, the CTL responses induced in heterozygous KI mice were similar to those in homozygous KI mice. These results suggest that coexpression of H-2 class I does not affect HLA-restricted CTL responses in HLA KI mice, which differs from the situation reported for monochain HLA Tg × β2m-/-mice. Furthermore, we generated double KI mice harboring two different HLA (HLA-A*2402 and HLA-A*0301) KI alleles, which showed a CTL response against both HLA-A24 and HLA-A3 epitopes when immunized with a mixture of both peptides. These results indicated that this HLA class I KI mouse model provides powerful research tools not only for the study of HLA class I-restricted CTL responses, but also for preclinical vaccine evaluation.
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan nm-harada@taiho.co.jp.
authors.forename: Naomoto
authors.initials: N
authors.lastname: Harada
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Satoshi
authors.identifier: 0000-0002-6856-4844
authors.initials: S
authors.lastname: Fukaya
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Hiroshi
authors.identifier: 0000-0003-0158-1743
authors.initials: H
authors.lastname: Wada
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Goto
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Osada
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ikizawa
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Motomu
authors.identifier: 0000-0001-7542-4172
authors.initials: M
authors.lastname: Sakuragi
authors.affiliation: Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Nobuyuki
authors.identifier: 0000-0002-7851-0081
authors.initials: N
authors.lastname: Oda
mesh_terms: D000818:Animals; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016133:Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000235:genetics*
chemical_list: D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin