The binding and presentation of peptide antigens by class I major histocompatibility molecules

The requirements for peptide binding by the human MHC Class I molecule HLA-B*0702 were investigated. Microcapillary HPLC electrospray ionization tandem mass spectrometry was used to sequence 15 peptides eluted from HLA-B*0702. Sequence alignment implicated four peptide positions in specific interactions with the class I molecule, and their importance was confirmed using synthetic peptides. Because no crystal structure for HLA-B*0702 was available, computer assisted modeling was used to understand novel aspects of peptide binding specificity and to accurately predict the effect of changes in peptide structure. The results demonstrate that mass spectrometric sequencing and computer assisted modeling can be used in absence of a crystal structure to make accurate predictions concerning requirements for peptide binding to class I molecules. HLA-B*0702 is a common human class I allele and has been implicated as an important restriction element for response to HTV-1, human papilloma virus, and malaria. These techniques may be valuable in order to predict or engineer T cell epitopes to be used against these pathogens.; Peptide priming can be an effective means of stimulating cytotoxic T cell responses in vivo, and it is clear that there is a relationship between the MHC affinity for peptide antigens and the ability of the immune system to recognize these antigens and respond. However, the relationship of class I affinity for peptide to the avidity of the T cell response has not been investigated. We explore this issue using several peptide antigens that differ in affinity for HLA-A*0201. Peptide stimulation of T cells in vivo with human melanoma tumor antigens from tyrosinase (369-377), YMDGTMSQV, or gp100 (280-288), YLEPGPVTA, induces cytotoxic responses in a murine transgenic system. The T cell avidity of these responses is inversely related to the MHC affinity of these antigens. Immunization with peptide antigens from human papilloma virus, and derivatives of antigens from hepatitis B core antigen suggest that this inverse relationship is a general phenomenon. This novel relationship is an important consideration for peptide stimulation of T cell responses because T cells that recognize peptide antigens with high avidity have been shown to be more efficacious in vivo than lower avidity T cells.