Hybrid HLA-DC antigens provide molecular evidence for gene trans-complementation

In the mouse there are hybrid determinants for the immune region (Ir) of the genome which contribute to the diversity of class II (Ia) antigens of the major histocompatibility complex (MHC) and provide a molecular basis for Ir gene complementation. In man, two prominent families of Ia molecule, HLA-DR and HLA-DC (or DS), have been identified which are respectively homologous to the murine I-E (E alpha, E beta) and I-A (A alpha, A beta) antigens. Whereas DR antigens consist of a constant alpha-chain and an extremely polymorphic beta-chain, both the alpha and beta subunits of DC antigens are structurally variable when different alleles are compared. The marked differences in the structure of the alpha- and beta-chains of HLA-DC molecules result in electrophoretic variants which allow the haplotype of origin of each subunit to be identified by two-dimensional gel electrophoresis. We report here that gene trans-complementation occurs in cells heterozygous for the HLA-D region, resulting in the expression of hybrid HLA-DC molecules in addition to the parental forms. Generation of new HLA-D region hybrid molecules contributes to the qualitative diversity of human MHC class II antigens and has important functional implications in immune regulation.