Structural requirements and biological significance of interactions between peptides and the major histocompatibility...

Previous studies indicate that T cells recognize a complex between the major histocompatibility complex (MHC) restriction-element and peptide-antigen fragments. Two aspects of this complex formation are considered in this paper: (1) what is the nature of the specificity of the interactions that allows a few MHC molecules to serve as restriction elements for a large universe of antigens; and (2) what is the relative contribution of determinant selection (i.e. antigen-MHC complex formation) and T-cell repertoire in determining the capacity of an individual to respond to an antigen? By analysing single amino acid substitution analogues of a peptide antigen (Ova 325-335) as well as by analysing the structural similarities between unrelated peptides capable of binding to the same MHC molecule, we have been able to document the very permissive nature of the antigen-MHC interaction. Despite this permissiveness of binding, it is possible to define certain structural features of peptides that are associated with the capacity to bind to a particular MHC specificity. With respect to the question of the relative role of 'determinant selection' and 'holes in the T-cell repertoire' in determining immune responsiveness, we present data that suggest both mechanisms operate in concert with one another. Thus only about 30% of a collection of peptides that in sum represent the sequence of a protein molecule were found to bind to Ia. Although immunogenicity was restricted to those peptides that were capable of binding to Ia (i.e. determinant selection was operative), we found that about 40% of Ia-binding peptides were not immunogenic (i.e. there were also 'holes in the T-cell repertoire').