The topic of this section is approaches to enhance or potentiate the immune response to vaccines. We can take advantage of what has been learned about antigen processing and presentation to try to actually alter the antigen itself in order to enhance immunogenicity or cross-reactivity of the antigen that is going to be used as a vaccine. As background, first I would like to review a few points made by Ron Germain about antigen processing elsewhere in this volume. CD8 cytotoxic T cells recognize antigens synthesized within or otherwise introduced into the cytoplasm of the cell.’-4 Antigens in the cytoplasm of the cells are cleaved by cytoplasmic proteases into peptide fragments, which are transported by an active transporter process, mediated by molecules encoded in the MHC itself, into the endoplasmic reticulum where they bind to newly synthesized class I molecules. As Germain pointed out, the peptide forms an integral part of the complex of MHC class I heavy chain and beta-2 microglobulin and peptide, which is then transported out to the cell surface where the T cell recognizes the combination of peptide and MHC.

With CD4 helper T cells, the class I molecule is replaced by a class I1 molecule, and the processing pathway is slightly different in that it usually involves antigens taken up from outside the cell and processed in endosomes where the peptide fragments bind to class I1 MHC molecules that are then transported out to the~ urface.~*’*~ However, in either case, the net result is that the T cell is seeing the combination of a peptide fragment of an antigen and an MHC molecule. This is the critical feature that determines everything else that I will discuss. The peptide binds in the groove of the MHC molecule between two alpha helices that form the sides of the With the class I1 molecule, the two sides of the groove are actually bounded by portions formed from two different subunits rather than two domains of the same subunit or the same polypeptide chain, as with class I molecules. Nevertheless, the overall structure is fairly similar. The peptide interacts with side chains of amino acid residues, both on the sides and on the floor of this peptide-binding groove. A few critical features have been discovered in Ian Wilson and Don Wiley’s laboratories and others. With class I molecules, the peptide seems to be anchored in particular at its two The NH,-terminal alpha amino group fits in a pocket at one end of the groove and the COOH-terminal carboxyl group fits in a pocket at the other end of the groove. This tethers the two ends in a fixed position