Defective Antigen Processing in GILT-Free Mice

Marić, Maja; Arunachalam, Balasubramanian; Phan, Uyen; Dong, Chen; Garrett, Wendy S.; Cannon, Kurt S.; Alfonso, Christopher; Karlsson, Lars; Flavell, Richard A.; Cresswell, Peter

doi:10.1126/science.1065500

Cited by 244 publications

(272 citation statements)

References 18 publications

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“…Western blotting confirmed the previous DGE results, indicating that large lipid vesicles resided in compartments that only became LAMP-1 positive after 20-min chase and also that these compartments were accessible to transferrin receptor, as a marker of recycling compartments, throughout the time course (23). The isolated phagosomes also contained MHC class II; H2-M, a chaperone of class II peptide loading (17); and GILT, a thiol-reductase necessary for Ag processing before peptide loading (24). Collectively, these data argue strongly that delivery of Ag in large vesicles enhances its retention in a prelysosomal compartment that is capable of efficient processing and presentation of OVA.…”

Section: Analysis Of the Ag Processing In Macrophagessupporting

confidence: 61%

“…The requirement for trafficking of liposomal Ag to lysosomes made previously was based on the requirement for reduction of disulphide bonds in Ags for processing to begin (30). In this context, it is significant that one of the components found in the large lipid vesicle phagosome was the recently described GILT (24), which has been demonstrated to be essential to perform this function. To our knowledge, this is the first time this enzyme has been identified in phagosomes.…”

Section: Discussionmentioning

confidence: 99%

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Vesicle Size Influences the Trafficking, Processing, and Presentation of Antigens in Lipid Vesicles

Brewer

Pollock

Tetley

et al. 2004

The Journal of Immunology

120

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Although it is accepted that particulate Ags are more immunogenic than soluble Ags in vivo, it is unclear whether this effect can be explained solely through enhanced uptake by APCs. In this study we demonstrate that vesicle size modulated the efficiency of Ag presentation by murine macrophages and that this effect was accompanied by a profound change in trafficking of Ag. Ag prepared in large particles (560 nm) was delivered into early endosome-like, immature phagosomes, whereas smaller vesicles (155 nm) and soluble Ags localized rapidly to late endosomes/lysosomes. However, peptide/class II complexes could be detected in both compartments. Phagosomes formed on uptake of large vesicles recruit Ag-processing apparatus while retaining the characteristics of early endosomes. In contrast, smaller vesicles bypassed this compartment, appeared to go more rapidly to lysosomal compartments, and exhibited reduced Ag-presenting efficiency. We conclude that the ability of phagocytosed, particulate Ag to target early phagosomes results in more efficient Ag presentation.

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Section: Analysis Of the Ag Processing In Macrophagessupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Vesicle Size Influences the Trafficking, Processing, and Presentation of Antigens in Lipid Vesicles

Brewer

Pollock

Tetley

et al. 2004

The Journal of Immunology

120

View full text Add to dashboard Cite

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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%

“…The structural complexity of a protein, especially the presence of disulfide bonds, is an important determinant in its presentation on MHC class II molecules [17,18]. Disulfide bonds impede access of processing proteases until reduced by specialized lysosomal enzymes such as IFN-+ -induced lysosomal thioreductase (GILT) [19][20][21]. This impediment prolongs the time required for presentation and may bias a T cell response towards epitopes contained within accessible regions of the protein.…”

Section: Introductionmentioning

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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“…16 Exogeneous engulfed proteins delivered into the endosomal/ lysosomal network are also exposed to distinct endosomal/lysosomal aspartyl and cysteine proteases including cathepsin S, 16 peptidases and reductases, such as the gamma-interferon inducible lysosomal thiol reductase GILT, yielding peptide ligands for HLA class II molecules. 17,18 In the MIIC, the exchange of CLIP for such antigenic high-affinity peptides is facilitated by low pH, endosomal proteases and the assistance of the non-classical MHC class II molecule HLA-DM. The latter serves as a peptide editor.…”

Section: Organization Of the Hla Class II Antigen-processing Machinerymentioning

confidence: 99%

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

2017

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The human leukocyte antigen (HLA) class II antigen-processing machinery (APM) presents to cognate CD4 C T-cells antigenic peptides mainly generated from exogeneous proteins in the endocytic compartment. These CD4 C T cells exert helper function, but may also act as effector cells, thereby recognizing HLA class II antigen-expressing tumor cells. Thus, HLA class II antigen expression by tumor cells influences the tumor antigen (TA)-specific immune responses and, depending on the cancer type, the clinical course of the disease. Many types of human cancers express HLA class II antigens, although with marked differences in their frequency. Some types of cancer lack HLA class II antigen expression, which could be due to structural defects or deregulation affecting different components of the complex HLA class II APM and/or from lack of cytokine(s) in the tumor microenvironment. In this review, we have summarized the information about HLA class II antigen distribution in normal tissues, the structural organization of the HLA class II APM, their expression and regulation in malignant cells, the defects, which have been identified in malignant cells, and their functional and clinical relevance.

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Defective Antigen Processing in GILT-Free Mice

Cited by 244 publications

References 18 publications

Vesicle Size Influences the Trafficking, Processing, and Presentation of Antigens in Lipid Vesicles

Vesicle Size Influences the Trafficking, Processing, and Presentation of Antigens in Lipid Vesicles

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

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

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