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Lysosomal cysteine proteases regulate antigen presentation

Nature Reviews Immunology volume 3, pages 472–482 (2003)Cite this article

Key Points

  • Lysosomal cysteine proteases regulate antigen presentation by both MHC class II molecules and the MHC class-I-like molecule CD1D.

  • Asparagine endopeptidase initiates invariant-chain (Ii) degradation in bone-marrow-derived antigen-presenting cells (APCs), but this is not the only protease that can mediate this cleavage step.

  • Late-stage degradation of Ii is mediated by cathepsin S in peripheral APCs, and cathepsin L in cortical thymic epithelial cells (TECs).

  • In bone-marrow-derived APCs, some peptide epitopes can be positively or negatively regulated by cathepsin S or asparagine endopeptidase.

  • Cathepsin L influences the peptide–MHC class II repertoire expressed by cortical TECs independently of its role in Ii degradation, implicating it as an important protease for the generation of a large number of MHC class-II-bound peptides.

  • The activity of cathepsin L is specifically inhibited in B cells, dendritic cells and macrophages stimulated by interferon-γ, indicating that cathepsin S must regulate Ii degradation in these peripheral APCs.

  • Cathepsin L is required for the presentation of CD1d ligands by thymocytes, eliciting the development of Vα14+Jα18+ natural killer T cells.

Abstract

Antigen presentation by both classical MHC class II molecules and the non-classical MHC class I-like molecule CD1D requires their entry into the endosomal/lysosomal compartment. Lysosomal cysteine proteases constitute an important subset of the enzymes that are present in this compartment and, here, we discuss the role of these proteases in regulating antigen presentation by both MHC class II and CD1D molecules.

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Figure 1: The MHC class II antigen-presentation pathway.
Figure 2: Degradation of invariant chain.
Figure 3: The role of cathepsin L in determining the peptide–MHC class II repertoire.
Figure 4: Regulation of lysosomal cysteine protease activity.
Figure 5: Lysosomal cysteine proteases and the CD1d antigen presentation pathway.

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Acknowledgements

We would like to thank C. Beers and P. Gough for critical review of the manuscript. A. Y. R. is supported by the Howard Hughes Medical Institute and grants from the National Institutes of Health.

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Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Immunology, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    Karen Honey & Alexander Y. Rudensky

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  1. Karen Honey
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Correspondence to Karen Honey.

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DATABASES

LocusLink

cathepsin B

cathepsin C

cathepsin D

cathepsin E

cathepsin F

cathepsin L

cathepsin S

cathepsin V

CD1d

CD4

CD8

CIITA

cystatin C

GILT

IFN-γ

Ii

Ly49a

NK1.1

Glossary

SUBSTRATE-ANALOGUE INHIBITORS

Small molecules that mimic the natural enzyme substrate and covalently bind to the cysteine residue present in the active site of the cysteine protease.

CLASS II TRANSACTIVATOR

(CIITA). A non-DNA-binding transcriptional activator that functions as a master control factor for the expression of MHC class II molecules. It is believed that CIITA alone provides the tissue specificity for the expression of MHC class II molecules and the accessory molecules invariant chain and HLA-DM (H–2M in mice).

NATURAL KILLER T CELLS

NKT cells constitute a lymphocyte subset that is defined by co-expression of the NK-cell marker NK1.1 and an αβ T-cell receptor (TCR). As a result of the heterogeneity of this population, this T-cell subset is in the process of being more precisely defined; for example, in the mouse, most of these cells are CD1d restricted and express a semi-invariant TCR (Vα14+Jα18+) and the CD4 co-receptor.

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Honey, K., Rudensky, A. Lysosomal cysteine proteases regulate antigen presentation. Nat Rev Immunol 3, 472–482 (2003). https://doi.org/10.1038/nri1110

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