Regulation of CD1 Function and NK1.1+ T Cell Selection and Maturation by Cathepsin S

Riese, Richard J.; Shi, Guo Ping; Villadangos, José A; Stetson, Daniel B.; Driessen, Christoph; Lennon-Duménil, Ana María; Chu, Ching-Liang; Naumov, Yuri N.; Behar, Samuel M.; Ploegh, Hidde L.; Locksley, Richard M.; Chapman, Harold A.

doi:10.1016/s1074-7613(01)00247-3

Cited by 75 publications

(59 citation statements)

References 46 publications

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“…[51], Mice lacking cathepsin S also showed defects in NKT cell selection in one [52] but not in another study [51]. Riese et al, suggested that thymic DC are also involved in NKT cell selection and that the accumulation of class II/Ii intermediates seen in cells lacking cathepsin S perturbs DC endosomal compartments through which CD1d molecules traffic [52].…”

Section: Lysosomal Proteases and T-cell Developmentmentioning

confidence: 99%

“…The key substrate(s), however, have not been identified. Interestingly, in this study the use of radiation bone marrow chimeras demonstrated that thymocytes could acquire cathepsin L produced by neighbouring thymic stromal cells similar to the acquisition of cathepsin G by B cells discussed in Antigen processing and presentation.[51], Mice lacking cathepsin S also showed defects in NKT cell selection in one [52] but not in another study [51]. Riese et al, suggested that thymic DC are also involved in NKT cell selection and that the accumulation of class II/Ii intermediates seen in cells lacking cathepsin S perturbs DC endosomal compartments through which CD1d molecules traffic [52].…”

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confidence: 92%

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Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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Section: Lysosomal Proteases and T-cell Developmentmentioning

confidence: 99%

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confidence: 92%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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“…Cat S-deficient APCs strongly accumulate p10 and display a delayed transport of MHC class II molecules to their surface. This inability to process Ii chain properly profoundly affects the immune system of Cat S Ϫ/Ϫ mice (5,(12)(13)(14). Several additional cysteine proteases, such as Cat L, Cat F, and Cat K, have been shown to be also expressed in murine APCs and to degrade Ii chain (at least in vitro) (15)(16)(17).…”

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confidence: 99%

Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs

Bania

Gatti

Lelouard

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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MHC class II-restricted antigen presentation plays a central role in the immune response against exogenous antigens. The association of invariant (Ii) chain with MHC class II dimers is required for proper antigen presentation to CD4 ؉ T cells by antigen-presenting cells. MHC class II complexes first traffic through the endocytic pathway to allow Ii chain degradation and antigenic peptide loading before their arrival at the cell surface. In recent years, a considerable effort has been directed toward the identification of proteases responsible for Ii chain degradation. Targeted gene deletion in mice has allowed a precise description of the cysteine proteases involved in the last step of Ii chain degradation. By using nonspecialized cellular models expressing MHC II molecules, we are now exploring the contribution of known cysteine proteases to human Ii chain processing. Surprisingly and contrary to the situation in mouse, cathepsin S was found to be the only human cysteine protease able to efficiently degrade the Ii-p10 fragment in epithelial cells. This selectivity has implications for thymic selection and indicates that differences between man and mice are probably more profound at this level than expected.antigen presentation ͉ lysosome ͉ protease

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“…1), were also upregulated upon treatment by the synthetic PPARg agonist RSG. Cathepsins are lysosomal proteinases, of which both cathepsin L and S have been implicated in lipid Ag presentation in mice (28,29). However, no role for CatD in lipid Ag presentation has been reported to date.…”

Section: Resultsmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ-Regulated Cathepsin D Is Required for Lipid Antigen Presentation by Dendritic Cells

Nakken

Varga

Szatmári

et al. 2011

The Journal of Immunology

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It is well established that dendritic cells (DCs) take up, process, and present lipid Ags in complex with CD1d molecules to invariant NKT cells. The lipid-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), has previously been shown to regulate CD1d expression in human monocyte-derived DCs, providing a link between lipid metabolism and lipid Ag presentation. We report that PPARγ regulates the expression of a lysosomal protease, cathepsin D (CatD), in human monocyte-derived DCs. Inhibition of CatD specifically reduced the expansion of invariant NKT cells and furthermore resulted in decreased maturation of saposins, a group of lipid transfer proteins required for lysosomal lipid Ag processing and loading. These results reveal a novel mechanism of lipid Ag presentation and identify CatD as a key component of this machinery and firmly place PPARγ as the transcriptional regulator linking lipid metabolism and lipid Ag processing.

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Regulation of CD1 Function and NK1.1+ T Cell Selection and Maturation by Cathepsin S

Cited by 75 publications

References 46 publications

Diverse regulatory roles for lysosomal proteases in the immune response

Diverse regulatory roles for lysosomal proteases in the immune response

Human cathepsin S, but not cathepsin L, degrades efficiently MHC class II-associated invariant chain in nonprofessional APCs

Peroxisome Proliferator-Activated Receptor γ-Regulated Cathepsin D Is Required for Lipid Antigen Presentation by Dendritic Cells

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