An acid protease secreted by transformed cells interferes with antigen processing.
The major excreted protein of malignantly transformed mouse fibroblasts (MEP), which is the precursor to lysosomal cathepsin L, was used to study the effect of exogenous acid proteases on antigen processing. When MEP and native pigeon cytochrome c were added to Chinese hamster ovary (CHO) cells expressing transfected major histocompatability complex class II gene products, the antigen-specific T-cell hybridoma 2B4 did not respond to the antigen. MEP appears to destroy the antigen in an acid compartment of the presenting cell because: (a) MEP is only active as a protease under acid conditions; (b) mannose 6-phosphate inhibited the internalization of MEP and blocked its effect on antigen processing; (c) the destruction required the simultaneous entry of the antigen and MEP into the cells; and (d) cytochrome c fragment 66-104 which does not need to be processed stimulated 2B4 in the presence of MEP. These results support the hypothesis that antigen processing requires internalization of the antigen into an acidic compartment, and they provide a new model for the investigation of the contribution of acid proteases to the reduced immunocompetence of tumor-bearing animals.
McCoy
K
K
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
Gal
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Schwartz
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Gottesman
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MM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology*; D000941:Antigens / Q000378:metabolism*; D002352:Carrier Proteins / Q000502:physiology; D056668:Cathepsin L; D002403:Cathepsins / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000503:physiopathology*; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003574:Cytochrome c Group / Q000276:immunology; D004705:Endocytosis; D010450:Endopeptidases / Q000502:physiology*; D000939:Epitopes; D006825:Hybridomas; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D017527:Receptor, IGF Type 2; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
D000941:Antigens; D002352:Carrier Proteins; D003574:Cytochrome c Group; D000939:Epitopes; D007376:Interleukin-2; D017527:Receptor, IGF Type 2; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse