Presentation of an exogenous protein antigen to helper (CD4+)T-lymphocytes by antigen presenting cells (APC) generally requires that the APCs degrade the native protein antigen into an immunogenic peptide, a process termed 'antigen processing', and that this peptide bind to a major histocompatibility complex (MHC) class II molecule. The complex of peptide and MHC molecule on the APC surface provides the stimulatory ligand for the alpha beta T cell receptor. The intracellular pathways and molecular mechanisms involved in the generation of the peptide-MHC complex are not well understood. Here, we describe several mutant APCs which are altered in their ability to present native exogenous protein antigens but effectively present immunogenic peptides derived from these proteins. The lesions in these mutants are not in the class II structural genes, but they affect the conformation of mature class II dimers.
Major histocompatibility complex (MHC) class II molecules are highly polymorphic 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 function provided by a gene mapping to the class II region of the HLA complex. The isolation of somatic cell mutants of antigen-presenting cells (APC) has shown that at least one gene which maps between HLA-DP and HLA-DQ, provisionally designated c2p-1 (ref. 3), mediates this process. Here we describe a unique new mutant 2.2.93, which manifests defective formation of class II/peptide complexes like that described in c2p-1 mutants. We show that (1) mutant 2.2.93 contains a mutation in HLA-DMA, and a representative c2p-1 mutant, 9.5.3, contains a mutation in HLA-DMB; and (2) transfection and expression of DMA complementary DNA in 2.2.93, and DMB cDNA in 9.5.3, reverses their mutant phenotypes. These results show that HLA-DMA and -DMB, genes of previously unknown function mapping between HLA-DP and HLA-DQ, 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 which is critical in the pathway of class II antigen presentation.
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