HLA-DMA AND HLA-DMB GENES ARE BOTH REQUIRED FOR MHC CLASS-II PEPTIDE COMPLEX-FORMATION IN ANTIGEN-PRESENTING CELLS

MAJOR histocompatibility complex (MHC) class II molecules are highly p olymorphic cell-surface glycoproteins that present antigenic peptides to CD4+ T lymphocytes. The normal assembly of class II molecules with cognate peptides for antigen presentation requires an accessory functi on provided by a gene mapping to the class II region of the HLA comple x1,2. The isolation of somatic cell mutants of antigen-presenting cell s (APC) has shown that at least one gene which maps between HLA-DP and HLA-DQ, provisionally designated c2p-1 (ref. 3), mediates this proces s1,2,4. Here we describe a unique new mutant 2.2.93, which manifests d efective formation of class II/peptide complexes like that described i n c2p-1 mutants. We show that (1) mutant 2.2.93 contains a mutation in HLA-DMA5, and a representative c2p-1 mutant, 9.5.3, contains a mutati on in HLA-DMB5; and (2) transfection and expression of DMA complementa ry DNA in 2.2.93, and DMB cDNA in 9.5.3, reverses their mutant phenoty pes. These results show that HLA-DMA and -DMB, genes of previously unk nown function mapping between HLA-DP and HLA-DQ5, are required for the normal assembly of peptides with MHC class II molecules. They suggest that HLA-DMA and -DMB encode subunits of a functional heterodimer whi ch is critical in the pathway of class II antigen presentation.