Proteases in MHC class I presentation and cross-presentation

Abstract

Cells that have mutated their genes or are virally infected are a potential threat to a host. Consequently, the immune system has evolved mechanisms for CD8 T lymphocytes to identify such cells and eliminate them. The generation of CD8 T cell responses occurs in two phases, both of which critically involve the process of Ag presentation. In the first phase, sentinel cells gather Ags present in tissues and then present them to naive CD8 T cells in ways that stimulate their maturation into effectors. In the second phase, these effector cells seek out and eliminate the pathological cells. The abnormal cells are identified through their presentation of immunogenic Ags that they are producing. The Ag presentation mechanisms used by the sentinel cells can be different from those in other cells. This article will review these mechanisms with a focus in each case on how antigenic peptides are generated for presentation.

FIGURE 1

Schematic representation of the different proteases involved in antigen processing. The proteasomal degradation step can lead to the generation of a mature epitope, a precursor peptide with an N-terminal extension, or the destruction of the epitope. Precursor peptides can be further trimmed by aminopeptidases to generate a mature epitope. Alternatively amino and/or endo peptidase activities can lead to the destruction of the epitope.

FIGURE 2

Proteases in cross presentation. Upon uptake by dendritic cells or macrophages, exogenous Ag can be processed and presented on MHC class I molecules by two major pathways: the phagosome-to-cytosol pathway (left) and the vacuolar pathway (right). In the cytosolic pathway, proteasomes are the major proteases to generate the antigenic peptide fragments. These peptides can be further trimmed by aminopeptidases in the cytosol, ER and possibly an endosomal compartment (for details see fig.1). In the less well-understood vacuolar pathway, cathepsin S plays a key role in generating class I binding peptides. It is unclear whether other proteases (e.g. IRAP) are also involved.