Lysosomal Cysteine Proteases and Antigen Presentation

A. Rudensky, C. Beers

5.1 Introduction 82

5.2 The MHC Class II Pathway 82

5.3 Lysosomal Cysteine Proteases 85

5.4 MHC Class II Invariant Chain Degradation by Lysosomal Cysteine Proteases 87

5.5 Role of Cathepsin S and L in Generation of MHC Class II-Bound Peptides 89

5.6 Regulation of Cathepsin S and L Activity and Their Role in Ii Degradation in Macrophages 90

5.7 Role of Cathepsin S and L in MHC Class II Presentation by Nonprofessional Antigen-Presenting Cells 91

References 92

Abstract. Lysosomal proteinases are involved in two critical stages of MHC class Il-mediated antigen presentation, i.e., degradation of invariant chain, a chaperone molecule critical for MHC class II assembly and transport, and generation of class Il-binding peptides in the endocytic compartment. We found that two lysosomal cysteine proteinases, cathepsins S and L, were found to be differentially expressed in different types of "professional" and "nonprofessional" antigen presenting cells, including B cells, macrophages, specialized thymic epithelium, intestinal epithelium, and dendritic cells. In this chapter, our recent studies on the role of cathepsin S and L in MHC class II-mediated antigen processing and presentation in these cells types are highlighted.

5.1 Introduction

T lymphocytes recognize antigens in the form of short peptides bound to major histocompatibility complex (MHC) molecules displayed on the surface of antigen-presenting cells (APCs). MHC molecules sample products of proteolysis in two major sites of constitutive protein breakdown within the cells: MHC class I molecules present peptides generated in the cytosol and MHC class II molecules present peptides generated in the endosomal/lysosomal compartment. Peptides presented by MHC class I are recognized by CD8+ T cells, while peptides generated in the endosomal/lysosomal compartment are presented in the context of MHC class II to CD4+ T cells (Cresswell 1994).

CD4+ T cell development is dependent upon recognition of self-MHC class II-peptide complexes in the thymus by TCR receptors expressed on immature thymocytes. Thymocytes capable of recognition of relatively low avidity MHC class II-self-peptide ligands expressed on cortical TECs proceed further with their differentiation program. Thy-mocytes displaying TCR with a high avidity for MHC class II-peptide complexes, expressed primarily by thymic bone marrow-derived cells, are subjected to deletion via apoptosis in the process dubbed negative selection. Elimination of these precursors of autoreactive T cells serves as a critical mechanism of autoimmunity prevention. Dendritic cells represent the most efficient type of bone marrow-derived antigen-presenting cells mediating negative selection in the thymus and presenting foreign and self-antigens in the periphery.

In this review, we discuss results of our recent studies of proteolytic mechanisms involved in MHC class II-mediated pathway of antigen presentation. Specifically, we focus on the role of lysosomal cysteine proteinases cathepsin S and L in maturation of MHC class II molecules and antigen processing in different types of antigen-presenting cells (APCs), including thymic cortical epithelial cells, dendritic cells, B cells, macrophages, and intestinal epithelial cells.

5.2 The MHC Class II Pathway

MHC class II molecules are constitutively expressed on the surface of professional antigen-presenting cells (APCs) of the immune system, i.e.,

B cells, dendritic cells (DCs), macrophages (M^s), and cortical thymic epithelial cells (TECs), which present proteolytic fragments of self and foreign protein antigens to the CD4+ T helper cells (Cresswell 1994; Watts 1997; Steimle et al. 1994). Expression of MHC class II can also be transiently induced by inflammatory signals in other cell types such as endothelial cells, fibroblasts, and different types of epithelial cells (Hershberg and Mayer 2000; Sartor 1994).

MHC class II molecules assemble in the endoplasmic reticulum with the help of the chaperone molecule invariant chain (Ii), a type II gly-coprotein that promotes the proper folding and assembly of the MHC a/p heterodimer (Anderson and Miller 1992; Cresswell 1996) (Fig. 1). Alpha-beta heterodimers associate with the Ii binding to a particular region of Ii, termed CLIP (class II-associated Ii peptide), within the peptide-binding groove. The roles of Ii include stabilization of the nascent MHC class II heterodimers and prevention of the premature binding of polypeptides or partially folded proteins within the ER. Ii also facilitates intracellular trafficking of newly synthesized MHC class II molecules to the endosomes. The latter function of Ii is mediated by its cytoplasmic tail, which contains an endosomal/lysosomal targeting motif (Bakke and Dobberstein 1990; Lotteau et al. 1990; see for review Cresswell 1996). Upon arrival at the endosomal/lysosomal compartment, the invariant chain is degraded by lysosomal proteases in a step-wise fashion. Initial cleavage results in generation of the p22 and p18 Ii degradation intermediates followed by generation of the p12 fragment, all of which are still associated with the a/p heterodimer. At the late stages of Ii degradation, the p12 fragment is removed, leaving only CLIP associated with the MHC class II peptide binding groove (Maric et al. 1994; Neefjes and Ploegh 1992; Riese et al. 1996) (Fig. 2). The MHC class II-like chaperone molecule HLA-DM (H-2M in mice) mediates removal of CLIP in exchange for the diverse array of peptides derived from self or foreign protein antigens generated in the endosomes and lysosomes. Upon peptide binding, MHC class II-peptide complexes traffic to the plasma membrane via a poorly understood mechanism or retrograde transport from the late aspects of the endosomal/lysosomal compartment (Denzin and Cresswell 1995; Martin et al. 1996) (Fig. 1). Thus, lysosomal proteases are involved in two critical processes within

Antigen

Plasma Membrane

Antigen

iLJL

/CD4+ cell

/CD4+ cell

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