Humanized transgenic mice expressing HLA DR4-DQ3 haplotype: reconstitution of phenotype and HLA-restricted T-cell responses

Chen, Z; de Kauwe, AL; Keech, C; Wijburg, O; Simpfendorfer, K; Alexander, WS; McCluskey, J

Author(s): Chen, Z; de Kauwe, AL; Keech, C; Wijburg, O; Simpfendorfer, K; Alexander, WS; McCluskey, J;
Details: Publication Year 2006-09,Volume 68,Issue #3,Page 210-219
Journal Title: TISSUE ANTIGENS
Publication Type: Journal Article
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 V beta 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.
Publisher: WILEY-BLACKWELL
Keywords: DEPENDENT DIABETES-MELLITUS; MAJOR HISTOCOMPATIBILITY COMPLEX; YEAST ARTIFICIAL CHROMOSOMES; COLLAGEN-INDUCED ARTHRITIS; CLASS-II MOLECULES; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSE; BETA-CHAIN; DQ GENES; SUSCEPTIBILITY
Publisher's Version: https://doi.org/10.1111/j.1399-0039.2006.00656.x
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Creation Date: 2006-09-01 12:00:00