Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis

Delamarre, Lélia; Couture, Rachael; Mellman, Ira; Trombetta, E. Sergio

doi:10.1084/jem.20052442

Cited by 181 publications

(161 citation statements)

References 31 publications

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“…They can also attenuate protease activity, at least in newly formed phagosomes, by raising phagosomal pH, which protected antigen for subsequent cross-presentation on class I MHC molecules [38]. In the same vein, eliminating specific enzymes [39] or making antigens more protease resistant [40] can improve antigen presentation and immunogenicity. Destructive processing events may not only limit immunogenicity but might also compromise the establishment of tolerance to self-proteins [30,41] but this remains to be proven.…”

Section: Antigen Processing and Presentationmentioning

confidence: 99%

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: 99%

Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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“…3A). This behavior is characteristic for immunogenic proteins 19 and again more similar to Bet v 1 18 than to Api g 1 which was degraded after 24 h (Fig. 3B).…”

Section: Discussionmentioning

confidence: 69%

“…In contrast, the α4β1‐integrin (very late antigen‐4) has been implicated in the recruitment of T cells to extraintestinal sites of inflammation, such as lungs and skin 17. We also determined T‐cell‐activating regions of Dau c 1 and subjected the protein to endolysosomal degradation as stability to lysosomal proteolysis has been considered a relevant factor for immunogenicity 18, 19. The resulting proteolytic fragments were sequenced by mass spectrometry and compared with the identified T‐cell‐activating regions.…”

mentioning

confidence: 99%

Characterization of the T-cell response to Dau c 1, the Bet v 1-homolog in carrot

Zulehner

Nagl

Briza

et al. 2016

Allergy

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BackgroundIn contrast to other Bet v 1‐related food allergens, the major carrot allergen, Dau c 1, has been suggested to induce food allergy independently from Bet v 1. As T cells are crucial in the sensitization process, we sought to characterize the T‐cell response to Dau c 1 and its cross‐reactivity with Bet v 1.MethodsDau c 1‐specific T‐cell lines (TCL) and clones (TCC) established from PBMC of birch pollen‐allergic patients with carrot allergy were analyzed for reactivity to Bet v 1, epitope specificity, allergen‐induced cytokine secretion, and expression of integrins α4β7 and α4β1, critical for gut and lung homing, respectively. mRNA expression of GATA3 and Tbet was analyzed in sorted CD3+ CD4+ CFSE low cells proliferating upon stimulation of PBMC with Dau c 1 or Bet v 1. Dau c 1 was incubated with endolysosomal proteases, and the resulting fragments were identified by mass spectrometry.ResultsAmong 14 distinct T‐cell‐activating regions, Dau c 1139–153 was recognized by 55% of the patients. Only 6 of 15 (40%) Dau c 1‐specific TCL and 9 of 21 (43%) TCC reacted with Bet v 1. Bet v 1‐nonreactive TCC were mainly Th1‐like and showed a higher expression of the integrin β7 and a significantly lower expression of the integrin β1 than Bet v 1‐positive TCC. A Th1‐like response was also detected in Dau c 1‐reactive CD3+ CD4+ CFSE low cells. Full‐length Dau c 1 was still detectable after 48 h of endolysosomal degradation. Proteolytic fragments of Dau c 1 matched its T‐cell‐activating regions.ConclusionDau c 1 displays several characteristics of sensitizing allergens, namely a major T‐cell‐activating region, low susceptibility to endolysosomal degradation, and induction of a Bet v 1‐independent T‐cell response. These cellular insights confirm that the major carrot allergen has a special status among Bet v 1‐related food allergens.

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“…Opsonized cells taken up via FcγRs undergo reduced processing in the phagosomes, a process termed as phagosome maturation [31]. Altered degradation of antigens in DCs may facilitate both the induction of antibody responses [32] as well as T cell immunity [33]. Antigen uptake in the form of immune complexes or opsonized cells is associated with enhanced antigen presentation by DCs and the generation of antigen specific T cells [34][35][36][37].…”

Section: Role Of Fcγr Balance In Adaptive Immunitymentioning

confidence: 99%

Role of chaperones and FcγR in immunogenic death

Dhodapkar

2008

Current Opinion in Immunology

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Cell death under physiologic conditions does not lead to the induction of immunity. However recognition of stressed or opsonized cells can trigger immune responses. Recent studies have begun to illustrate the critical role of molecular chaperones such as inducible heat shock proteins in mediating immunogenicity of stressed cells. Immunity to opsonized cells depends in part on the engagement and the balance of activating and inhibitory FcγRs on antigen presenting dendritic cells. Understanding both these pathways of immunogenic cell death may yield novel approaches to regulate immunity. Two forms of immunogenic cell deathBillions of cells die each day and are replaced by newly differentiated progeny. Corpses of such dying cells are rapidly removed by phagocytes; do not elicit immunity and may induce tolerance. However under some settings, recognition of dying cells leads to inflammatory responses and immunity[1] • . Two aspects of such "immunogenic death" are the focus of this review. A common response to cellular stress is the transcriptional activation of molecular chaperones that belong to the class of inducible heat shock proteins (HSPs). Another setting wherein dying cells might induce immunity is when they are opsonized by antibodies due to antibody mediated recognition of determinants on dying cells. Such opsonized cells can be recognized by FcγR mediated pathways on antigen presenting cells (APCs). Below, we will discuss recent insights into how both of these pathways play an important role in regulating immunogenicity of dying cells and can be dysregulated in autoimmunity. Heat shock proteins (HSPs) and immunogenic cell deathHSPs are referred to as stress proteins or molecular chaperones, although most HSPs are constitutively expressed. Known best for their roles in regulating intracellular protein homeostasis, HSPs were immunologically implicated because of the observations that tumor-derived HSPs, although having no tumor-specific mutations, can immunize for tumor-specific T cell immunity [2] • . Efforts to explain the phenomenon have led to two

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Enhancing immunogenicity by limiting susceptibility to lysosomal proteolysis

Cited by 181 publications

References 31 publications

Diverse regulatory roles for lysosomal proteases in the immune response

Diverse regulatory roles for lysosomal proteases in the immune response

Characterization of the T-cell response to Dau c 1, the Bet v 1-homolog in carrot

Role of chaperones and FcγR in immunogenic death

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