Characteristics of peptides which compete for presented antigen-binding sites on antigen-presenting cells

The T cell recognition of globular protein antigens requires the cell surface presentation of the protein by Ia-expressing antigen-presenting cells (APC). The mechanisms by which APC function remain to be elucidated. To gain a better understanding of association of antigen with APC surfaces, a large panel of peptides of diverse physicochemical properties was assayed for the ability to compete with presented antigen for binding sites on the APC surface. Competition was measured by the ability of a peptide to block the I-Ek-restricted T cell response to pigeon cytochrome c (Pc) as presented by APC. The panel assayed included overlapping peptides representing the entire length of sperm whale myoglobin and the α and β chains of human adult hemoglobin as well as synthetic conformational peptides of lactate dehydrogenase C4 exhibiting stable secondary, α-helical structures. The results presented hereshow that several peptides of this group compete with the presented form of Pc forbinding sites on the APC. However, there is no single biochemical property or amino acid sequence algorithm which predicts the blocking ability. The peptides which compete with presented Pc are not predicted to assume the amphipathic α-helical conformation hypothesized by De Lisi and Berzofsky (Proc. Natl. Acad. Sci. USA 1986. 82: 7048) for T cell antigenic peptides. However, peptides designed and synthesized to adopt a stable α-helical secondary structure show more potent blocking activity than the corresponding linear peptides, suggesting that the secondary structure may indeed be a contributing factor in the ability of presented antigenic peptides to be bound by the APC. The results with the myoglobin and hemoglobin peptides show no connection between any particular secondary structure of the peptide in the native proteins and the ability of the peptides to block presentation. Further, there is no correlation between the major histocompatibility complex restriction of the competing peptides and their ability to block the I-Ek-restricted Pc-specific T cell response. This suggests that antigen presented by the APC may be bound to APC structures other than Ia prior to association with Ia. Such additional binding sites for presentedantigen may be necessary to facilitate association with Ia.