Hill, Christopher Mark; (1991) Analysis of structural features of peptide MHC protein complexes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

To help determine possible mechanisms by which MHC molecules bind a diverse but limited range of peptides, the interactions between peptides and MHC proteins have been studied using two different systems. A predictive algorithm, based on empirical analysis of known T-cell epitopes, was used to locate determinants in the L1, E6, and E7 open reading frames (ORF) of human papilloma virus (HPV) type 16. Peptides containing putative determinants were synthesised and assayed for lymphoproliferative activity in mice. The T cells elicited were highly specific for HPV type 16, but were also found to exhibit degenerate MHC restriction, indicating that some of the peptides were able to form immunogenic complexes with different MHC proteins. The contact residues and conformational features of a panel of different peptides bound to HLA DR1Dw1 were determined by analysing the ability of analogues containing long chain biotinylated lysine substituted at each position, to bind both the MHC protein and labelled avidin. The structural and conformational features of each of the peptides when bound to the HLA molecule were unique. However, three of the peptides originally defined by HLA-DR1Dw1 restricted T cells, shared several conformational features, while the remaining three peptides defined by T cells restricted through other alleles, shared some but not all of these features. Critical contact residues identified within the determinants were used to align their sequences and revealed structural homology between the peptides at positions making contact with the MHC protein. A similar pattern of residues was found in a large number of other determinants known to bind to different MHC loci and alleles. The data suggested a common structural mechanism by which many peptides bind to MHC proteins. Knowledge of this mechanism should enable the rational design of MHC binding peptides for the development of both vaccines and autoimmune disease therapies.

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