DMA AND DMB ARE THE ONLY GENES IN THE CLASS-II REGION OF THE HUMAN MHC NEEDED FOR CLASS II-ASSOCIATED ANTIGEN-PROCESSING

Previous studies have shown that homozygous mutations between the LMP2 and DNA loci in the human MHC cause class II molecules to be abnormal ly conformed and unstable in the presence of SDS at low temperature, a nd impede class II-associated Ag processing and presentation. These ab normalities result from impaired ability to form intracellular class I I/peptide complexes that predominate in normal cells. We show in this work that this defect results from deficient expression of either the DMA or the DMB gene. Human B-LCL.174 (DR3) cells, which have a deletio n of all known expressible genes in the class II region, express trans gene-encoded HLA-DR3, but have the abnormalities. Transfer of cosmid H A14, which contains the DMA and DMB genes, into.174 (DR3) cells restor ed normal DR3 conformation, stability in 0.4% SDS at 0 degrees, and ab ility to process and present tetanus toroid, but only when both DMA an d DMB mRNAs were present. The requirement for both genetic expressions in engendering normal phenotypes was confirmed by transferring the cl oned genes into.174 (DR3) cells separately or together. Because normal phenotypes were fully restored in transferent cells expressing DMA pl us DMB, other genes in the similar to 1-mb homozygous class II region deletion in.174 (DR3) cells either do not participate in or are dispen sable for apparently normal production of intracellular class II/pepti de complexes. The properties of DM-deficient EBV-transformed B lymphob lastoid cell lines (LCLs) suggest ways of identifying humans in whom D M deficiency contributes to congenital immunodeficiency and malignancy .