Generation of major histocompatibility complex class I antigens: functional interplay between proteasomes and TPPII

The proteasome is key in the cascade of proteolytic processing required for the generation of peptides presented at the cell surface to cytotoxic T lymphocytes by major histocompatibility complex class I molecules. Proteasome-dependent epitope processing is greatly improved through the interferon-gamma-induced formation of immunoproteasomes and the activator complex PA28. Tripeptidyl aminopeptidase II also has a strong effect on epitope generation. With its endoproteolytic and exoproteolytic activities, TPPII acts 'downstream' of the proteasome and relies on products released by the proteasome. The antigen-processing cascade involving different proteolytic systems raises anew the question of how antigenic peptides are generated. We therefore revisit the interferon-gamma-induced immune adaptation of the proteasome and attempt to redefine its function in connection with the emerging importance of TPPII.