Proteases involved in MHC dass II antigen presentation

Abstract

Summary: Major histocompatibility complex class II antigen presentation requires the participation of lysosomal proteases in two convergent processes. First, the antigens endocytosed by the antigen‐presenting cells must be broken down into antigenic peptides. Second, class II tnolecules are synthesized with their peptide‐binding site blocked by invariant chain (li), and they acquire the capacity to bind antigens only after Ii has been degraded in the compartments where peptides reside. The study of genetically modified tnice deficietit in single lysosomal proteases has allowed us to determine their role in these processes, Cathepsins (Cat) B and D. previously considered major players in MHC class II antigen presentation, are dispensable for degradation of Ii and for generation of several antigenic determinants. By contrast, Cat S plays an essential role in removal of Ii in B cells and dendritic cells, whereas Cat L apparently does so in thymic epithelial cells. Accordingly, the absence of Cat S and L have major consequences for the onset of humoral immtine responses and for T‐cell selection, respectively. It is likely that other as yet uncharacterized lysosomal enzymes also play a role in Ii degradation and in generation of antigenic determinants. Experiments involving drugs that interfere with protein traffic suggest that more than one mechanism for Ii removal, probably involving different proteases, can co‐exist in the same antigen‐presenting cell. These findings may allow the development of protease inhibitors with possible therapeutic applications.

Dissection of the HLA-DR4 Peptide Repertoire in Endocrine Epithelial Cells: Strong Influence of Invariant Chain and HLA-DM Expression on the Nature of Ligands

“…Functional class II expression is highly dependent on the expression of two main chaperones, the invariant chain (Ii) and DM. Newly synthesized class II ␣-and ␤-chains form a nonameric complex with three Ii molecules in the endoplasmic reticulum (ER) (9) where Ii blocks the peptidebinding groove (10) and guides class II dimers to the endocytic pathway where Ii is proteolytically cleaved leaving the CLIP fragment bound to class II (11). Peptide loading and editing mainly occurs in late endocytic compartments designated MHC II-containing compartments (12).…”

Molecular Interaction and Enzymatic Activity of Macrophage Migration Inhibitory Factor with Immunorelevant Peptides

“…Antigen processing consists of protein denaturation and fragmentation. Several proteases have been described to be part of this system (17). Proteins that contain disulfide bonds require an additional processing step, the reduction of the cysteine residues to produce antigenic peptides (18).…”

The role of proteases in pathologies of the synovial joint

“…The immune cells (B cells, T cells, dendritic cells and macrophages) of the rheumatoid pannus are believed to be involved in antigen presentation, antibody production and cytokine generation. An important role in antigen presentation has been identified for cathepsin S, which is involved in both the processing of endocytosed proteins to peptides suitable for presentation and the cleavage of the invariant chain to CLIP during MHC class II maturation (Riese et al, 1996;Shi et al, 1999;Villadangos et al, 1999). Studies of cathepsin S knockout mice revealed a decrease in their susceptibility to collagen-induced arthritis and impaired invariant chain processing in both dendritic cells and B cells (Nakagawa, Brissette et al, 1999).…”