EXPRESSION OF HLA-DR4 AND HUMAN CD4 TRANSGENES IN MICE DETERMINES THEVARIABLE REGION BETA-CHAIN T-CELL REPERTOIRE AND MEDIATES AN HLA-DR-RESTRICTED IMMUNE-RESPONSE

Inherited susceptibility to rheumatoid arthritis is associated with ge nes encoding the human major histocompatibility complex class II molec ule HLA-DR4. To study the immune function of HLA-DR4 and attempt to ge nerate a murine model of rheumatoid arthritis we have produced triple transgenic mice expressing HLA-DRA0101, -DRB1*0401, and human CD4. Th e expression of the HLA transgenes is driven by the promoter of the mu rine major histocompatibility complex class II I-E alpha gene and was found on murine cells that normally display major histocompatibility c omplex class II molecules. The expression of the human CD4 transgene i s driven by the murine CD3 delta-promoter, and therefore its gene prod uct was found on cells that express murine CD3. In contrast to other H LA-DR and HLA-DQ transgenic mouse lines, the transgenes are functional in our mice. In H-2 I-E-negative transgenic mice, T cells expressing variable region beta chain (V beta) 3, 5, 6, 7, 9, 11, 12, or 13 were either absent or significantly reduced, in contrast to H-2 I-E-negativ e nontransgenic littermates. In addition, the peptide antigen influenz a A virus hemagglutinin 307-319, which binds to the HLA-DRA0101/-DRB1 0401 heterodimer with high affinity and induces an HLA-DR-restricted and CD4(+) T-cell response in humans, also induced a T-cell response i n the triple transgenic mice but not in nontransgenic littermates. Thu s, these transgenic mice should permit extensive testing of the antige n-presentation capabilities of the HLA-DRA0101/-DRB1*0401 molecule.