Interactions among polymorphic and conserved residues in MHC class II proteins affect MHC-peptide conformation and T cell recognition.

The structural basis for MHC-restricted T cell recognition of the N-terminal peptide of myelin basic protein (MBP Ac1-11) presented by two mouse class II alleles, Ak and Au, was examined, focusing on the roles of A beta chain polymorphic residues 38 beta (in the beta sheet) and 61 beta (in the alpha helix) in controlling the responses of panels of Ak- and Au-restricted T cell hybridomas. Despite the conservative nature of the substitutions at 38 beta (k = Val, u = Leu) and 61 beta (k = Trp, u = Tyr), transfectants expressing Ak or Au proteins carrying allelic substitutions at 38 beta and/or 61 beta gave dramatically reduced T cell responses. The modest reduction in peptide binding detected using a biotinylated MBP peptide analog appear insufficient to explain the reduced responses, suggesting that changes at 38,61 beta create conformational changes in the MHC-peptide complex. The impact of allelic substitutions at 38,61 beta on T cell responses is also modulated by other residues differing between Ak and Au. To explore the structural basis for these phenomena, protein models were developed of the Ak, Au and 38,61 beta mutant proteins using self-consistent ensemble optimization methodologies. Substitutions of the alternative allelic residue at 38 beta and/or 61 beta, which are in van der Waals contact, change the configuration of this region of the peptide-binding groove, and potentially might affect the conformation of the bound peptide and its hydrogen-bonding to residue 61 beta. The models predict that this region of the groove is markedly altered by allelic differences at A beta residue 9 beta (k = His, u = Val) which determine the position of the side-chain of Tyr30 beta, adjacent to residues 38 beta and 61 beta. Thus, interactions among polymorphic and conserved residues control the antigen presentations functions of MHC class II proteins.