Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells

Fonteneau, Jean-François; Kavanagh, Daniel G.; Lirvall, Margareta; Sanders, Catherine J.; Cover, Timothy L.; Bhardwaj, Nina; Larsson, Marie

doi:10.1182/blood-2003-06-1801

Cited by 113 publications

(81 citation statements)

References 54 publications

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“…In contrast, blocking the ER-to-PM transport by H89 had only a limited effect on T cell recognition. Although cathepsins are able to produce peptide products with suitable MHC-anchor residues (20), it was suggested that cathepsin-generated precursor peptides require further downstream trimming by the proteasome to generate mature peptide Ags of permissible length (22). In accordance with this idea, we found that silencing of TAP1 or inhibition of the proteasome caused a strong reduction in the T cell stimulation, suggesting that cytosolic processing is also required for functional MHC I processing of chlamydial Ags.…”

Section: Discussionsupporting

confidence: 76%

“…Cathepsin D and S are two well-characterized endovacuolar asparticand cysteine-type hydrolases, respectively, which are expressed in many cells of the immune system (72). Both hydrolases are known to function as important downstream proteases in autolysosomal/ amphisomal degradation (73,74) in the endovacuolar MHC IIpresentation pathway (75)(76)(77)(78) and are thought to be functionally involved in DCs in the alternative generation of antigenic MHC I peptides (20)(21)(22). In this context, it is interesting to note that autophagosomal processes regulate the expression and activity of amphisomal cathepsins (79).…”

Section: Discussionmentioning

confidence: 99%

“…Vacuolar crosspresentation is an alternative pathway that is independent of the proteasome and TAP and requires endovacuolar cathepsins (20,21). A variation of this latter pathway has been proposed in which Ags undergo cathepsin-dependent preprocessing in late endosomal compartments before they are transported to the cytosol where they are further processed by the proteasome (22). Thus, it seems that multiple pathways coexist and that they functionally cooperate with each other (23).…”

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confidence: 99%

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Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Fiegl

Kägebein

Liebler-Tenorio

et al. 2013

The Journal of Immunology

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Dendritic cells (DCs) are among the first professional APCs encountered by the obligate intracellular bacterium Chlamydia during infection. Using an established mouse bone marrow–derived DC line, we show that DCs control chlamydial infection in multiple small inclusions characterized by restricted bacterial growth, impaired cytosolic export of the virulence factor chlamydial protease–like activity factor, and interaction with guanylate-binding protein 1, a host cell factor involved in the initiation of autophagy. During maturation of infected DCs, chlamydial inclusions disintegrate, likely because they lack chlamydial protease–like activity factor–mediated protection. Released cytosolic Chlamydia are taken up by autophagosomes and colocalize with cathepsin-positive amphisomal vacuoles, to which peptide transporter TAP and upregulated MHC class I (MHC I) are recruited. Chlamydial Ags are subsequently generated through routes involving preprocessing in amphisomes via cathepsins and entry into the cytosol for further processing by the proteasome. Finally, bacterial peptides are reimported into the endosomal pathway for loading onto recycling MHC I. Thus, we unravel a novel pathway of MHC I–mediated cross-presentation that is initiated with a host cellular attack physically disrupting the parasitophorous vacuole, involves autophagy to collect cytosolic organisms into autophagosomes, and concludes with complex multistep antigenic processing in separate cellular compartments.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Fiegl

Kägebein

Liebler-Tenorio

et al. 2013

The Journal of Immunology

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“…Another study on cross-presentation identified a requirement for cathepsin D in human DC that had taken up apoptotic or necrotic monocytes expressing vaccinia-encoded flu matrix protein [24]. Cathepsin D appeared to be acting upstream of the proteasome in this system.…”

Section: Antigen Processing and Presentationmentioning

confidence: 95%

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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“…The resulting apoptotic bodies are taken up by neighboring DC leading to a process of antigen sharing [16]. DC are highly specialized in moving endocytic contents into their cytoplasm [17][18][19][20][21][22], and we hypothesized that uptake of free viral cores or apoptotic bodies or exosomes containing viral cores could lead to transduction of the engulfing DC. As this would lead to continued priming through multiple cycles of engulfment, vaccination with DC transduced with such a vector would induce strong, specific T and B cell responses against vector constituents.…”

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confidence: 99%

Induction of HIV‐specific T and B cell responses with a replicating and conditionally infectious lentiviral vaccine

2008

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The development of an HIV vaccine that induces broad and potent immunity is critically needed. Viruses, including lentiviruses, have been used as vectors for ex vivo transduction of antigens into dendritic cells (DC). We hypothesized that DC transduced with a vector that allows selective infection of DC could induce potent immunity by continually priming DC. A lentiviral vector encoding HIV gag-pol without env would form viral cores in transduced DC, but would release non-infectious particles by budding into endosomes and releasing apoptotic bodies or exosomes containing viral cores. DC function by endocytosing DCderived apoptotic bodies, and they are specialized in their ability to move endocytic contents into the cytoplasm. We postulated that endocytosis of vector cores could lead to transduction of a second round of DC. In this report, we demonstrate accumulation of viral cores inside transduced DC and show second-round transduction of immature DC that endocytose transduced DC in vitro. The effectiveness of immunization of mice with transduced DC to induce specific lymphocyte activation was assessed. Mice developed antigen-specific T cell responses and specific antibodies after immunization. Transduction of DC with a replication-competent but conditionally infectious lentivirus could be a novel vaccine strategy for HIV.Key words: Dendritic cell Á HIV Á Immune response Á Lentiviral vector Introduction A safe and effective vaccine for HIV is critically needed to combat the worldwide scourge of AIDS. While the correlates of immune protection have yet to be clearly defined, either for protective or therapeutic vaccines, it is widely believed that both CD4 + and CD8 + T cell as well as humoral immunity are important. How sufficiently broad, potent, and sustained responses can be elicited has yet to be determined, and this represents a critical gap in our understanding of how to generate an effective vaccine such that protective or therapeutic immunity can be achieved. Selection and activation of lymphocytes is a function of antigen presentation by dendritic cells (DC), making DC a logical vehicle for immunotherapy [1]. Early studies showed that DC loaded with tumor extracts [2,3] or antigenic peptides [2][3][4][5] induced anti-tumor immunity in both laboratory mice [2,4,5] and human melanoma patients [3]. More recently, viruses have been used as gene transfer vectors for the ex vivo transduction of DC with selected antigens. Lentiviral vectors have a number of advantages over adenoviruses, adeno-associated viruses, poxviruses, and alphaviruses. Transduction is stable due to chromosomal integration and non-dividing cells are efficiently transduced [6]. Lentivirally transduced DC have been studied for their ability to induce anti-tumor immunity. Breckpot et al. [7] demonstrated that murine DC transduced with a lentivirus encoding a truncated variant of ovalbumin (OVA) protected against tumor challenge with OVA-expressing cells. He et al. [8] recently described the transduction of murine DC with a lentiviral vector...

show abstract

Characterization of the MHC class I cross-presentation pathway for cell-associated antigens by human dendritic cells

Cited by 113 publications

References 54 publications

Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Diverse regulatory roles for lysosomal proteases in the immune response

Induction of HIV‐specific T and B cell responses with a replicating and conditionally infectious lentiviral vaccine

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