Low CD4+ T cell responses to the C-terminal region of the malaria merozoite surface protein-1 may be attributed to processing within distinct MHC class II pathways

Quin, Stuart; Cross, Caroline; Berg, Matthias; Lindo, Vivian; Stockinger, Brigitta; Langhorne, Jean

doi:10.1002/1521-4141(200101)31:1<72::aid-immu72>3.0.co;2-z

Cited by 34 publications

(26 citation statements)

References 39 publications

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“…We have previously suggested that the relatively poor immunogenicity of this part of MSP1 is caused by its structural complexity, as it was only available for loading onto recycling MHC class II molecules after reduction of its disulfides [24]. In both human and rodent malaria, T cell responses are biased towards parts of MSP1 N-terminal to MSP1 19 [24][25][26]. Here we investigate the ability of asparagine endopeptidase (AEP) [27], one of the major lysosomal proteases responsible for antigen processing, to digest MSP1 19 from two different rodent malaria parasites and determine whether removal of disulfide bonds by reduction and alkylation allows faster processing and faster antibody response in vivo.…”

Section: Introductionsupporting

confidence: 88%

“…This inhibition correlated with a significant impediment in the development of antibody responses in vivo, and supports our earlier observation that T cell responses to MSP1 19 are accelerated if the antigen is reduced and alkylated [24].…”

Section: Discussionmentioning

confidence: 99%

“…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. These results were in agreement with our earlier observation that APC require a significantly longer time to present native MSP1 19 to a T cell hybridoma than R/A protein, but that the hybridoma could be activated by peptides derived from either antigen [24].…”

Section: Discussionmentioning

confidence: 99%

“…MSP1 19 is a highly disulfide-constrained protein, comprising two epidermal growth factor (EGF)-like domains with five or six disulfide bonds [22,23]. We have previously suggested that the relatively poor immunogenicity of this part of MSP1 is caused by its structural complexity, as it was only available for loading onto recycling MHC class II molecules after reduction of its disulfides [24]. In both human and rodent malaria, T cell responses are biased towards parts of MSP1 N-terminal to MSP1 19 [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…For example, mice lacking the enzyme IFN␥-inducible lysosomal thiol reductase show defective antigen presentation of MHC class II-restricted T-cell responses to a number of protein antigens (30). Cleavage of disulfide bonds during antigen processing was also shown to be a crucial step in determining the availability of several T-cell epitopes within the merozoite surface protein-1 of Plasmodium chabaudi chabaudi (29). However, the participation of this particular enzyme may not be an invariable feature of antigen presentation, given that the amino acid sequence of PA does not include any cysteine residues.…”

Section: Fig 2 the Kinetics Of Presentation Of Cd4mentioning

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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Regulation of peptide presentation by major histocompatibility complex class II molecules at the surface of macrophages

et al. 2003

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We studied major histocompatibility complex class II-dependent presentation of two T cell epitopes delivered as synthetic peptides by fixed macrophages. Treatment of bone marrow macrophages with inhibitors of proteinases of the metallo-, aspartic and serine proteinase families enhanced presentation of peptides, indicating that several enzyme families participate in destructive antigen processing of exogenous peptides. High performance liquid chromatography and mass spectrometry analysis demonstrated the presence of peptide fragments in macrophage supernatants, and permitted identification of the cleavage sites which confirmed the enzyme families involved. Peptide fragments were shown to be competitive inhibitors of presentation of the full-length peptide to CD4 T cells by fixed and live macrophages. The results indicate that several classes of proteinases can modulate antigen presentation by at least two mechanisms: (1) degradation of extracellular oligopeptides and (2) generation of natural peptide ligands that block antigen presentation to CD4 T cells. The generation of inhibitory natural peptide ligands is a new mechanism of immunoregulation which could operate during the induction of T cell responses in a variety of situations.

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Low CD4+ T cell responses to the C-terminal region of the malaria merozoite surface protein-1 may be attributed to processing within distinct MHC class II pathways

Cited by 34 publications

References 39 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

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

Regulation of peptide presentation by major histocompatibility complex class II molecules at the surface of macrophages

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