Fertilized oocytes were co-injected with two DNA fragments: a human CD4 cDNA joined to the promoter from the human CD2 gene and a large DNA fragment, reassembled from segments of the cosmid pDCbeta2, containing the human major histocompatibility (MHC) class II alleles HLA-DQA1*0301 and HLA-DQB*0302, which together encode the dimer comprising the HLA-DQ8 molecule, plus 5' regulatory elements. Human CD4 is expressed at a low level on all T cells of transgenic mice. HLA-DQ8 is expressed in homozygous NOD mice at a level comparable to that of the endogenous NOD H2-Abetag7 MHC class II molecule in wild-type NOD mice.