HLA-DQ allelic polymorphisms constrain patterns of class II heterodimer formation
Kwok, W.W.; Kovats, S.; Thurtle, P.; Nepom, G.T.
Journal of Immunology 150(6): 2263-2272
1993
ISSN/ISBN: 0022-1767 PMID: 8450211 Document Number: 411740
HLA-DQ class II molecules are complex heterodimers in which polymorphic alpha- and beta-polypeptides form noncovalent associations leading to cell surface expression. Using gene transfer with retroviral vectors, we demonstrate that surface expression of heterodimers among various DQ-alpha and -beta polypeptides is not universal. Two types of allele-specific constraints were found: DQ-beta chains that are associated with the DQw1 specificities do not form stable cell surface heterodimers with DQ-alpha chains encoded on haplotypes that are associated with DQw2, DQw3, or DQw4. Similarly, surface expression of heterodimers composed of DQw2- or DQw3-associated DQ-beta chains and DQw1 DQ-alpha chains were not detected. The formation of mixed isotype heterodimers also showed allelic preference: DR-alpha/DQw1-beta dimers were detected on the cell surface, but DR-alpha/DQw3-beta dimers were not. Failure to express class II heterodimers on the cell surface was apparently due to either inefficient assembly of the alpha- and beta-chains or retention of the mismatched dimers in an intracellular compartment. DQ-beta cDNA encoding DQw1- and DQw3-associated beta-polypeptides were modified to create chimeric expression vectors in which portions of the DQ-beta polypeptides were exchanged between different alleles. The resulting chimeric DQ-beta polypeptides were tested for their ability to form stable heterodimers with different DQ-alpha polypeptides. A cluster of polymorphic amino acid residues encoded by the 3' end of the DQB1 second exon, corresponding to residues 60 to 91 in the DQ-beta polypeptide, were found to be critical determinants constraining stable cell surface heterodimer formation among preferential alpha- and beta-combinations.