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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.

Type

Journal article

Journal

J Immunol

Publication Date

15/07/2006

Volume

177

Pages

983 - 990

Keywords

Animals, Cell Line, Tumor, Cross-Priming, Epitopes, T-Lymphocyte, Female, Graft Rejection, H-2 Antigens, H-Y Antigen, Histocompatibility Antigen H-2D, Immunologic Surveillance, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Minor Histocompatibility Antigens, Multienzyme Complexes, Proteasome Endopeptidase Complex, Proteins, Sex Factors, Skin Transplantation, T-Lymphocyte Subsets