A closer look at proteolysis and MHC-class-II-restricted antigen presentation

Lennon-Duménil, Ana-María; Bakker, Anke; Wolf-Bryant, Paula; Ploegh, Hidde L.; Lagaudrière-Gesbert, Cécile

doi:10.1016/s0952-7915(01)00293-x

Cited by 120 publications

(102 citation statements)

References 58 publications

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“…The native, but not the R/A, MSP1 19 was also resistant to the proteolytic activity of whole lysosomal extracts, suggesting that other proteases present cannot substitute for the activity of AEP under these conditions. Parts of the lysosomal antigen-processing machinery may not function optimally at the pH and dilution used here, and particularly the role of IFN-+ -induced lysosomal thioreductase (GILT) in the 'unlocking' of cystines [21,35] will need to be assessed for MSP1 19 . However, AEP processing of native MSP1 19 did not produce any different peptides than those from the R/A protein, merely less of a smaller repertoire.…”

Section: Discussionmentioning

confidence: 99%

Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response

Hensmann

Moss

et al. 2004

Eur J Immunol

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The 19 kDa C‐terminal fragment of the malaria parasite merozoite surface protein 1 (MSP119) is a leading malaria vaccine candidate. In rodents, high antibody levels to this protein confer protective immunity, and can be generated by immunization with the antigen in adjuvants. In natural human infections, however, MSP119‐specific antibody responses can be short‐lived andcomparatively low, despite repeated exposure to infection. The tightly folded structure of MSP119 is stabilized by five or six disulfide bonds. These bonds impede antigen processing and, thereby, may affect the generation of CD4+ T cells providing help for B cells. Asparagine endopeptidase could digest unfolded, but not native MSP119 in vitro. Immunization with unfolded MSP119 resulted in a faster antibody response, and a combination of unfolded and native MSP119 increased antibody responses to the native form. Immunization with either form of the antigen activated similar numbers of CD4+ T cells, but, unlike the antibody response, CD4+ T cells immunized with one form of MSP119 were able to respond in vitro to the other form of the protein. Although the reduced form of MSP119 does not induce protective antibodies, our data suggest that inclusion of unfolded protein may improve the efficacy of MSP119 as a vaccine.See correction http://dx.doi.org/10.1002/eji.200490004

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Section: Discussionmentioning

confidence: 99%

Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response

Hensmann

Moss

et al. 2004

Eur J Immunol

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“…Proteolytic enzymes are found in the endolysosomes, at the cell surface and secreted into the extracellular phase. Enzymes from all these locations have a demonstrated capacity to participate in processing for MHC class II presentation [23][24][25]. We tested if DC secrete proteolytic enzymes that directly process the OVA protein into the SIINFEKL peptide for presentation on H2-K b .…”

Section: Ova Processing By Secreted Proteasesmentioning

confidence: 99%

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Chen

Jondal

2004

Eur J Immunol

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Exogenous proteins can be processed by antigen-presenting cells for the generation of MHC class I-restricted T cell responses. Where this occurs is not clear, although both transfer of internalized antigen into the cytosol and alternative processing in endolysosomes and phagosomes have been reported. Here we have studied the capacity of bone marrowderived mouse myeloid dendritic cells (DC) to process the OVA protein for peptide presentation by H2-K b . We have found that immature DC (iDC), both wild-type and transporter associated with antigen processing (TAP)-deficient cells, can transiently process OVA in a pathway which is resistant to inhibitors of the classical MHC class I pathway including the Golgi inhibitor Brefeldin A (BFA) and the proteasome inhibitor lactacystin. This alternative pathway is not found in subcultured DC with an intermediate maturity (imDC) or in resting, IL-3 expanded macrophages but can be re-expressed in imDC if these are activated by an immunostimulatory CpG oligonucleotide. Both iDC and CpG-activated DC were found to process OVA by regurgitation. In addition, we found that iDC secrete proteolytic enzymes into the supernatant, which can process OVA in the extracellular phase. These results suggest that multiple pathways exist for the processing of exogenous protein antigens into MHC class Ibinding peptides.

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“…ϩ T-cells are liberated from protein antigens following some form of antigen processing before they are accessible to bind MHC class II molecules usually in acidic endocytic compartments of antigen presenting cells (APC) such as macrophages, dendritic cells, and B cells (17)(18)(19)(20)(21)(22)(23)(24). Following uptake by APC, processing is thought to be initiated during transport through the endosomal system by unfolding of antigens induced by low pH (25,26), oxidation (27), disulphide reduction (28 -30), or limited cleavage by lysosomal enzymes such as asparaginyl endopeptidase (31).…”

mentioning

confidence: 99%

“…Following uptake by APC, processing is thought to be initiated during transport through the endosomal system by unfolding of antigens induced by low pH (25,26), oxidation (27), disulphide reduction (28 -30), or limited cleavage by lysosomal enzymes such as asparaginyl endopeptidase (31). Some or all of these steps may be essential to "unlock" or progressively expose protein antigens to further proteolytic degradation by lysosomal hydrolases, including cathepsins of the cysteine and aspartyl enzyme families (18,22). Serine proteinases have been implicated in antigen processing in the extracellular space for presentation of peptide epitopes on the surface of dendritic cells (32,33), but the role of serine proteinases in intracellular processing has not been studied in any detail (34 -36).…”

mentioning

confidence: 99%

Differential Processing of CD4 T-cell Epitopes from the Protective Antigen of Bacillus anthracis

Musson

Walker

Flick-Smith

et al. 2003

Journal of Biological Chemistry

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We have mapped CD4؉ T-cell epitopes located in three domains of the recombinant protective antigen of Bacillus anthracis. Mouse T-cell hybridomas specific for these epitopes were generated to study the mechanisms of proteolytic processing of recombinant protective antigen for antigen presentation by bone marrow-derived macrophages. Overall, epitopes differed considerably in their processing requirements. In particular, the kinetics of presentation, ranging from 15 (fast) to 120 min (slow), suggested sequential liberation of epitopes during proteolytic processing of the intact PA molecule. Pretreatment of macrophages with ammonium chloride or inhibitors of the major enzyme families showed that T-cell responses to an epitope presented with fast kinetics were unaffected by raising endosomal pH or inhibiting cysteine or aspartic proteinases, suggesting presentation independent of lysosomal processing. In contrast, responses to epitopes presented with slower kinetics were dependent on low pH and the activity of cysteine or aspartic proteinases indicating a requirement for lysosomal processing. In addition, responses to all epitopes, whether their presentation was dependent on low pH or not, were prevented by treatment of macrophages with broad spectrum serine proteinase inhibitors. Thus, our data are consistent with a model of sequential antigen processing within the endosomal system, beginning with a pre-processing step mediated by serine or metalloproteinases prior to further processing by lysosomal enzymes. Rapidly presented epitopes seemed to require only limited proteolysis at earlier stages of endocytosis, whereas the majority of epitopes required more extensive processing by neutral proteinases followed by lysosomal enzymes.

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A closer look at proteolysis and MHC-class-II-restricted antigen presentation

Cited by 120 publications

References 58 publications

Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response

Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Differential Processing of CD4 T-cell Epitopes from the Protective Antigen of Bacillus anthracis

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