The endosome-lysosome pathway and information generation in the immune system

Abstract

For a long time the lysosomal pathway was thought to be exclusively one for catabolism and recycling of material taken up by endocytosis from the external milieu or from the cytosol by autophagy. At least in the immune system it is clear now that endo/lysosomal proteolysis generates crucially important information, in particular peptides that bind class II MHC molecules to create ligands for survey by the diverse antigen receptors of the T lymphocyte system. This process of antigen processing and presentation is used to display not only foreign but also self peptides and therefore is important for 'self' tolerance as well as immunity to pathogens. Some cells, macrophages and particularly dendritic cells can load peptides on class I MHC molecules in the endosome system through the important, though still not fully characterised, pathway of cross-presentation. Here I try to provide a brief review of how this area developed focussing to some extent our own contributions to understanding the class II MHC pathway. I also mention briefly recent work of others showing that proteolysis along this pathway turns out to regulate immune signalling events in the innate immune system such as the activation of some members of the Toll-like receptor family. Finally, our recent work on the endo/lysosome targeted protease inhibitor cystatin F, suggests that auto-regulation of protease activity in some immune cells occurs. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.

Fig. 1

Antigen receptor directed antigen processing and ‘handover’ to class II MHC. The cartoon is meant to represent a class II MHC positive endo/lysosomal compartment in a B cell. BCR bound antigen (grey) with different potential T cell epitopes (coloured ovals) is delivered and processing commences whilst the antigen is still bound to the BCR. Scissors denote proteases. Limited cleavages produce large unfolded segments of antigen that can be captured by DM-chaperoned class II MHC molecules without release of antigen into the lumenal phase. Trimming (scissors) reduces the size of MHC associated antigen prior to delivery to the cell surface. NB vesicle trafficking steps not shown. The figure suggests that antigen fragments released into the lumen (orange) have a lower probability of survival and capture than fragments that are tethered by the antigen receptor and are membrane proximal (green). This scenario results in preferential presentation of some T cell epitopes over others. For experimental evidence see Ref. .

Fig. 2

Cystatin F as an attenuator of lysosomal cysteine proteases. Cystatin F (pale green) dimerises in the ER through di-sulphide linkages (yellow dots) and is transported to the endocytic pathway using the mannose-6-phosphate targeting system. Dimer to monomer conversion is driven by proteolytic action (red asterisk) on an N-terminal linking peptide that contains one of the cysteines involved in the disulphide bridge. Protease generated monomer has an N-terminus truncated by 15 residues relative to monomer generated by reducing agents in vitro. Since cystatin N-termini are important in cysteine protease inhibition, this changes the target range of the monomer. For example, cathepsin C is blocked by protease generated monomer but not by full-length monomer generated by reduction. Secreted cystatin F can be taken up, again via mannose-6-phosphate receptors and activated by bystander cells. For experimental evidence see references .