Important Role of Cathepsin S in Generating Peptides for TAP-Independent MHC Class I Crosspresentation In Vivo

Shen, Lianjun; Sigal, Luis J.; Boes, Marianne; Rock, Kenneth L.

doi:10.1016/j.immuni.2004.07.004

Cited by 334 publications

(340 citation statements)

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Section: Antigen Processing and Presentationmentioning

confidence: 56%

“…Cross-presentation can be TAP-dependent or less commonly, TAP-independent. Surprisingly, the absence of cathepsin S markedly compromised TAP-independent crosspresentation of both ovalbumin and influenza virus antigens consistent with a role for this enzyme in epitope generation [17].Interestingly, a recent study has linked Ii processing to DC migration. Compared with WT DC, those lacking Ii migrated faster to draining lymph nodes whereas DC lacking cathepsin S, which accumulates Ii, migrated more slowly [18].…”

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confidence: 57%

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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: Antigen Processing and Presentationmentioning

confidence: 56%

mentioning

confidence: 57%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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“…However, precise events at molecular level that are responsible for GM-CSFenhanced cross-presentation by CD8 1 DCs are currently unknown. There are many pathways leading to cross-presentation of antigens [23]: phagosome-to-cytosol [24], endosome-to-ER, ER-phagosome fusion [25,26], endosome-to-ER [27], as well as vacuolar pathway [28,29]. It remains a task to identify which pathway(s) is affected by GM-CSF.…”

Section: Discussionmentioning

confidence: 99%

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

et al. 2011

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Resident CD8 1 DCs perform several functions, including cross-presenting antigen and rapidly engulfing the Gram-positive intracellular pathogen Listeria monocytogenes. Little is known about how these functions of CD8 1 DCs are modulated. Here, we show that granulocyte-macrophage CSF (GM-CSF), a cytokine that exists at low levels at steady state but is elevated during infection and inflammation, enhances cross-presentation and rapid uptake of L. monocytogenes by resident CD8 1 DCs. This previously unrecognized functional enhancement of CD8 1 DCs by GM-CSF was independent of promoting DC survival in vitro. Enhancement of these functions by GM-CSF was also marked by CD103 expression on CD8 1 DCs that was strongly regulated by GM-CSF. Our findings not only identify GM-CSF as a key molecule regulating CD8 1 DC function, but also as a factor responsible for functional heterogeneity of CD8 1 DCs that is at least substantially demarcated by CD103 expression.Keywords: CD8 1 DC . CD103 . Cross-presentation . Granulocyte-macrophage colony-stimulating factor . Listeria monocytogenes Supporting Information available online IntroductionDCs found in the spleen can be grossly separated into CD8 1 DCs and CD8 À DCs. The latter includes CD8 À CD4 1 and CD8 À CD4 À conventional DCs and CD45RA 1 plasmacytoid DCs. Different DC subsets have different functions. Notably, the resident CD8 1 DCs show superior capacity for ingesting cell-associated antigens [1], for cross-presenting antigens (i.e. presenting exogenous antigens to CD8 1 T cells) [2][3][4], for the rapid uptake of certain bacterial pathogens [5] and for producing . It has been previously reported that a small proportion of CD8 1 DCs express the integrin CD103 and these CD103-expressing CD8 1 DCs are enriched in cells engulfing cellular antigens and cross-priming CD8 1 T cells [7]. However, it is unclear what regulates the above Ã Co-senior authors. Here, we investigated whether GM-CSF might influence the function of CD8 1 DCs and CD103 expression. Functionally, DCs from GM-CSF transgenic (GMtg) mice had enhanced crosspresentation, whereas in the absence of GM-CSF signaling, crosspresentation was reduced. Rapid uptake of Listeria monocytogenes by CD8 1 DCs was also reduced in the absence of GM-CSF. Phenotypically, we showed that bacterial infection preferentially increased CD103 expression by CD8 1 DCs and this increase was dependent on GM-CSF. Together, our results identify a critical role for GM-CSF in preferentially regulating expression of the integrin CD103 by CD8 1 DCs and in regulating certain functions of CD8 1 DCs. ResultsGM-CSF enhances cross-presentation by CD8 1 DCs GM-CSF is a cytokine that exists at very low levels at steady state but is greatly induced during infection and inflammation [13]. To understand the role of GM-CSF in regulating the functions of CD8 1 DCs, we chose mouse models with GM-CSF overexpression. We first compared the cross-presentation by CD8 1 DCs from GMtg mice and control littermates. When soluble OVA was used as the antigen in vitro, CD...

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“…There is evidence for TAP-independent pathways of Ag presentation by MHC class I molecules (4,5). The proteases involved include ER signal peptidase, trans-Golgi network furin and cathepsins for endogenously synthesized proteins (6 -10) and for internalized Ags (11)(12)(13)(14).…”

Section: Furin-processed Antigens Targeted To the Secretory Routementioning

confidence: 99%

“…The clinical phenotype of TAP-deficient human beings, who have a limited immunodeficiency with chronic respiratory bacterial infections, illustrates that the TAP-independent pathways may be sufficient to allow the control of viral infections. Indeed, in vivo TAPindependent priming of CD8 ϩ T lymphocytes has been demonstrated in TAP-deficient mice (14,(17)(18)(19) and human beings (20). There is a need, however, for quantitative evaluation of the contribution of these supplementary pathways to Ag presentation in vitro and in vivo.…”

Section: Furin-processed Antigens Targeted To the Secretory Routementioning

confidence: 99%

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

Medina

Ramos²,

Iborra³

et al. 2009

The Journal of Immunology

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Most pathogen-derived peptides recognized by CD8+ CTL are produced by proteasomes and delivered to the endoplasmic reticulum by the TAP transporters associated with Ag processing. Alternative proteases also produce antigenic peptides, but their actual relevance is unclear. There is a need to quantify the contribution of these supplementary pathways in vitro and in vivo. A well-defined TAP-independent secretory route of Ag processing involves the trans-Golgi network protease furin. Quantitation of this route by using OVA constructs encoded by vaccinia viruses indicates that it provides approximately one-third of all surface complexes of peptide and MHC class I molecules. Generation of the epitope carboxyl terminus is a dramatic rate-limiting step, since bypassing it increased efficiency by at least 1000-fold. Notably, the secretory construct activated a similar percentage of Ag-specific CD8+ T cells in wild type as in TAP1-deficient mice, which allow only secretory routes but which have a 10- to 20-fold smaller CD8 compartment. Moreover, these TAP1−/− OVA-specific CD8+ T lymphocytes accomplished elimination of epitope-bearing cells in vivo. The results obtained with this experimental system underscore the potential of secretory pathways of MHC class I Ag presentation to elicit functional CD8+ T lymphocytes in vivo and support the hypothesis that noncytosolic processing mechanisms may compensate in vivo for the lack of proteasome participation in Ag processing in persons genetically deficient in TAP and thus contribute to pathogen control.

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Important Role of Cathepsin S in Generating Peptides for TAP-Independent MHC Class I Crosspresentation In Vivo

Cited by 334 publications

References 58 publications

Diverse regulatory roles for lysosomal proteases in the immune response

Diverse regulatory roles for lysosomal proteases in the immune response

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

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Important Role of Cathepsin S in Generating Peptides for TAP-Independent MHC Class I Crosspresentation In Vivo

Cited by 334 publications

References 58 publications

Diverse regulatory roles for lysosomal proteases in the immune response

Diverse regulatory roles for lysosomal proteases in the immune response

GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8+ spleen dendritic cells

Furin-Processed Antigens Targeted to the Secretory Route Elicit Functional TAP1−/−CD8+ T Lymphocytes In Vivo

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GM‐CSF increases cross‐presentation and CD103 expression by mouse CD8⁺ spleen dendritic cells