Intracellular routes for antigen processing and presentation

Antigenic peptides bound by histocompatibility molecules are recognized by T cells during immune and autoimmune reactions and as tumour antigens. The peptides recognized and the nature of the T-cell responses during these processes were discussed throughout this symposium on Ir genes: From Biology to Medicine. Understanding the mechanism by which histocompatibility molecules bind to antigenic peptides can contribute to the design of vaccination strategies to enhance normal and anti-tumour immune responses and prevent autoimmune reactions. Initial studies toward this goal have focused on definition of the peptides recognized and the inherent specificity of the antigen-binding pockets in histocompatibility molecules. It has now become clear that this analysis must extend to an investigation of the intracellular events leading to the generation of antigenic peptides (antigen processing) and the association of those peptides with histocompatibility molecules (antigen presentation). The intracellular pathways contributing to antigen processing and presentation influence whether the peptide is presented by a class I or class II histocompatibility molecule, and therefore whether an antibody or a cellular immune response is initiated (Brodsky and Guagliardi, 1991). Antigenic peptides bound by class II molecules stimulate helper T cells (CD4 super(+)) and the antibody response, while antigenic peptides presented by class I molecules are recognized by cytotoxic T cells (CD8 super(+)). Class I and class II histocompatibility molecules are predicted to have a similar antigen-binding pocket (Brown et al., 1988) and can present the same antigenic peptides (Perkins et al., 1989). However, they acquire peptides generated in different intracellular locations. Class I molecules generally bind and present peptides that are derived from degradation of proteins synthesized by the cell in which the class I molecule is assembled and expressed (Townsend and Bodmer, 1989). Class II molecules can bind peptides derived from exogenous proteins internalized into the presenting cell (Unanue, 1984) as well as peptides from endogenously synthesized proteins (Sekaly et al., 1988). The specificity of class I and class II molecules for peptides from different intracellular sources is a result of differential assembly processes and intracellular trafficking of the two classes of molecules. Whether a peptide has access to class I or class II molecules depends on the degradation pathway that g