title: Humanized transgenic mice expressing HLA DR4-DQ3 haplotype: reconstitution of phenotype and HLA-restricted T-cell responses.
abstract: Many autoimmune conditions have close genetic linkages to particular human histocompatibility leukocyte antigen (HLA) class II genes. With the aim of establishing a murine model of autoimmune disease, we have generated an HLA DR4-DQ3 haplotype transgenic (Tg) mouse that expresses a 440-kb yeast artificial chromosome harbouring DRA, DRB1*040101, DRB4*010301, DQA1*030101, DQB1*0302 and all the internal regulatory segments. This Tg mouse line was crossed to human CD4 (hCD4) Tg mice and endogenous class II knockout mice (I-A(o/o) and I-E(o/o)) lines to generate a DR4-DQ3.hCD4.IAE(o/o) Tg line. The Tg DR and DQ molecules are expressed on the physiological cell types in these animals, i.e. on most B cells (>85%), dendritic cells (DCs) and macrophages but not on T cells, with levels of expression comparable with those of human B cells (where DR > DQ expression). The DR4/DQ3 transgenes fully reconstituted the CD4 T-cell compartment, in both the thymus and the periphery, and the analysis of the T-cell receptor repertoire in the Tg mice confirmed that these class II molecules were able to mediate thymic selection of a broad range of Vbeta families. HLA DR4- and DQ3-restricted T-cell responses were elicited following immunization with known T-cell determinants presented by these molecules. Furthermore, the DR4-DQ3-restricted CD4(+) T cells conferred protective antibody-mediated immunity against an otherwise lethal infection with Salmonella enterica var. typhimurium. These new DR4-DQ3 Tg mice should prove to be valuable tools for dissecting the importance of this class II haplotype in autoimmune disorders like rheumatoid arthritis.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: A L
authors.initials: AL
authors.lastname: de Kauwe
authors.forename: C
authors.initials: C
authors.lastname: Keech
authors.forename: O
authors.initials: O
authors.lastname: Wijburg
authors.forename: K
authors.initials: K
authors.lastname: Simpfendorfer
authors.forename: W S
authors.initials: WS
authors.lastname: Alexander
authors.forename: J
authors.initials: J
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D004195:Disease Models, Animal; D005838:Genotype; D006683:HLA-DQ Antigens / Q000096:biosynthesis* / Q000235:genetics; D015804:HLA-DR4 Antigen / Q000096:biosynthesis* / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D010641:Phenotype; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D014162:Transfection
chemical_list: D006683:HLA-DQ Antigens; C051569:HLA-DQ3 antigen; D015804:HLA-DR4 Antigen