title: Differential influence on cytotoxic T lymphocyte epitope presentation by controlled expression of either proteasome immunosubunits or PA28.
abstract: The proteasome is the principal provider of major histocompatibility complex (MHC) class I-presented peptides. Interferon (IFN)-gamma induces expression of three catalytically active proteasome subunits (LMP2, LMP7, and MECL-1) and the proteasome-associated activator PA28. These molecules are thought to optimize the generation of MHC class I-presented peptides. However, known information on their contribution in vivo is very limited. Here, we examined the antigen processing of two murine leukemia virus-encoded cytotoxic T lymphocyte (CTL) epitopes in murine cell lines equipped with a tetracycline-controlled, IFN-gamma-independent expression system. We thus were able to segregate the role of the immunosubunits from the role of PA28. The presence of either immunosubunits or PA28 did not alter the presentation of a subdominant murine leukemia virus (MuLV)-derived CTL epitope. However, the presentation of the immunodominant MuLV-derived epitope was markedly enhanced upon induction of each of these two sets of genes. Thus, the IFN-gamma-inducible proteasome subunits and PA28 can independently enhance antigen presentation of some CTL epitopes. Our data show that tetracycline-regulated expression of PA28 increases CTL epitope generation without affecting the 20S proteasome composition or half-life. The differential effect of these IFN-gamma-inducible proteins on MHC class I processing may have a decisive influence on the quality of the CTL immune response.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.lastname: van Hall T
authors.forename: A
authors.initials: A
authors.lastname: Sijts
authors.forename: M
authors.initials: M
authors.lastname: Camps
authors.forename: R
authors.initials: R
authors.lastname: Offringa
authors.forename: C
authors.initials: C
authors.lastname: Melief
authors.forename: P M
authors.initials: PM
authors.lastname: Kloetzel
authors.forename: F
authors.initials: F
authors.lastname: Ossendorp
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D009052:Leukemia Virus, Murine / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000276:immunology / Q000378:metabolism*; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D013450:Sulfones / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013752:Tetracycline / Q000494:pharmacology
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D001324:Autoantigens; D018797:Cell Cycle Proteins; D015853:Cysteine Proteinase Inhibitors; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; C099558:Ki antigen; D009097:Multienzyme Complexes; D011506:Proteins; C490050:Psme1 protein, rat; C490052:Psme2 protein, rat; D013450:Sulfones; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C486172:Tap1 protein, rat; C067713:lactacystin; C071313:LMP-2 protein; C009873:divinyl sulfone; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse; C490921:Psmb10 protein, rat; D013752:Tetracycline; D000111:Acetylcysteine