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Role of Immunoproteasomes in Cross-Presentation¹

Michael J. Palmowski^*, Uzi Gileadi^*, Mariolina Salio^*, Awen Gallimore^*, Maggie Millrain, Edward James, Caroline Addey, Diane Scott, Julian Dyson, Elizabeth Simpson and Vincenzo Cerundolo^*,2

^* Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; and Transplantation Biology Group, Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom

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.

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