INTERACTIONS AMONG POLYMORPHIC AND CONSERVED RESIDUES IN MHC CLASS-IIPROTEINS AFFECT MHC-PEPTIDE CONFORMATION AND T-CELL RECOGNITION

The structural basis for MHC-restricted T cell recognition of the N-te rminal peptide of myelin basic protein (MBP Ac1-11) presented by two m ouse class II alleles, A(k) and A(u), was examined, focusing on the ro les of A(beta) chain polymorphic residues 38(beta) (in the beta sheet) and 61(beta)(in the alpha helix) in controlling the responses of pane ls of A(k)- and A(u)-restricted T cell hybridomas. Despite the conserv ative nature of the substitutions at 38(beta) (k = Val, u = Leu) and 6 1(beta) (k = Trp, u = Tyr), transfectants expressing A(k) or A(u) prot eins carrying allelic substitutions at 38(beta) and/or 61(beta) gave d ramatically reduced T cell responses. The modest reduction in peptide binding detected using a biotinylated MBP peptide analog appear insuff icient to explain the reduced responses, suggesting that changes at 38 ,61(beta) create conformational changes in the MHC-peptide complex. Th e impact of allelic substitutions at 38,61(beta) on T cell responses i s also modulated by other residues differing between A(k) and A(u). To explore the structural basis for these phenomena, protein models were developed of the A(k), A(u) and 38,61(beta) mutant proteins using sel f-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). Th e models predict that this region of the groove is markedly altered by allelic differences at A(beta) residue 9(beta) (k = His, u = Val) whi ch determine the position of the side-chain of Tyr30(beta), adjacent t o residues 38(beta) and 61(beta). Thus, interactions among polymorphic and conserved residues control the antigen presentations functions of MHC class II proteins.