A Newly Recognized Pairing Mechanism of the α- and β-Chains of the Chicken Peptide–MHC Class II Complex

MHC class II (MHC-II) molecules play a crucial role in cellular and humoral immunity by forming peptide-MHC-II (pMHC-II) complexes. The three-dimensional structures of pMHC-II complexes have been well resolved in humans and mice. However, there is no structural information for pMHC-II complexes in nonmammals. In chickens, there are two closely related and highly polymorphic beta-chains and one monomorphic alpha-chain, and the mechanism by which one monomorphic alpha-chain combines with two polymorphic beta-chains to form a functional heterodimer remains unknown. In this study, we report the crystal structure of a chicken pMHC-II complex (pBL2*019:01) at 1.9-A resolution as the first nonmammalian structure of a pMHC-II complex. The structure reveals an increase in hydrogen bonding between the alpha and beta main chains at the central interface that is introduced by the insertion of four residues in the alpha-chain. The residues in the beta-chain that form hydrogen bonds with the alpha-chain are conserved among all beta alleles. These structural characteristics explain the phenomenon of only one BLA allele without sequence variation pairing with highly diverse BLB alleles from two loci in the genome. Additionally, the characteristics of the peptide in the peptide-binding groove were confirmed. These results provide a new understanding of the pairing mechanism of the alpha- and beta-chains in a pMHC-II complex and establish a structural principle to design epitope-related vaccines for the prevention of chicken diseases.