Structural Requirements for Pairing

The class II antigens ofthe human MHC are cell surface heterodimers composed of noncovalently linked 35-kD a chains and 29-kD (3 chains . These antigens are present on macrophages, B lymphocytes, and other APC (for review, see reference 1). Class II antigens are capable of binding immunogenic peptides and thereby serve as ligand for the TCR (2, 3) . Recent experiments have demonstrated that class II proteins are also functional ligands for the T cell surface antigen CD4 (4-6). Class 11 antigens display a very high degree ofallelic polymorphism, presumably to enable the species to mount the widest possible range of immune responses . At the individual level, diversity in class II antigens is provided by the existence ofthree isotypic forms in man, named HLA-DR, HLA-DQ, and HLA-DP. These isotypes are characterized by nonpolymorphic sequences unique to each isotypic a and a chain. HLA-DR, the immunodominant class II isotype, has a nonpolymorphic a chain andahighly polymorphica chain. Most ofthe allelic variation in DR achains is concentrated in three regions located in the NHz-terminal half of the molecule, termed the 01 domain. Extensive allelic variability is also located in the first domain of the DQa, DQ3, and DPS chains (7, 8) . A third form of diversity is possible if the a chain of one isotype pairs with the (3 chain of another, creating a so-called mixed isotypic pair. Such pairings have not been demonstrated on APC in vivo using available monoclonal and polyclonal serological reagents . The pair DRa/DQ3 has been found in particular transformed B cell lines that express high levels of the DR a chain (9). Modulation of the level ofexpression of DR achains in B cell lines controlled the formation of theDRa/DQ8 pair, in that only cells expressing high levels of DRamRNA produced this mixed isotypic pair (10) . Cell surface expression of mixed isotypic pairs was detected in cells transfected with different combinations ofa and 0 chains, presumably because high levels of mRNA for each chain were produced in those cells (11) .