title: Role of immunoproteasomes in cross-presentation.
abstract: The evidence that proteasomes are involved in the processing of cross-presented proteins is indirect and based on the in vitro use of proteasome inhibitors. It remains, therefore, unclear whether cross-presentation of MHC class I peptide epitopes can occur entirely within phagolysosomes or whether it requires proteasome degradation. To address this question, we studied in vivo cross-presentation of an immunoproteasome-dependent epitope. First, we demonstrated that generation of the immunodominant HY Uty(246-254) epitope is LMP7 dependent, resulting in the lack of rejection of male LMP7-deficient (LMP7(-/-)) skin grafts by female LMP7(-/-) mice. Second, we ruled out an altered Uty(246-254)-specific T cell repertoire in LMP7(-/-) female mice and demonstrated efficient Uty(246-254) presentation by re-expressing LMP7 in male LMP7(-/-) cells. Finally, we observed that LMP7 expression significantly enhanced cross-priming of Uty(246-254)-specific T cells in vivo. The observations that male skin grafts are not rejected by LMP7(-/-) female mice and that presentation of a proteasome-dependent peptide is not efficiently rescued by alternative cross-presentation pathways provide strong evidence that proteasomes play an important role in cross-priming events.
authors.affiliation: Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palmowski
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: Awen
authors.initials: A
authors.lastname: Gallimore
authors.forename: Maggie
authors.initials: M
authors.lastname: Millrain
authors.forename: Edward
authors.initials: E
authors.lastname: James
authors.forename: Caroline
authors.initials: C
authors.lastname: Addey
authors.forename: Diane
authors.initials: D
authors.lastname: Scott
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics; D006182:H-Y Antigen / Q000235:genetics; D064532:Histocompatibility Antigen H-2D; D007157:Immunologic Surveillance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D011506:Proteins / Q000235:genetics; D012737:Sex Factors; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D006182:H-Y Antigen; D064532:Histocompatibility Antigen H-2D; D015778:Minor Histocompatibility Antigens; D009097:Multienzyme Complexes; D011506:Proteins; C102450:Uty protein, mouse; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex