J. Exp. Med., Volume 189, Number 6, March 15, 1999 895-906

Modulation of Proteasomal Activity Required for the Generation of a Cytotoxic T Lymphocyte-defined Peptide Derived from the Tumor Antigen MAGE-3

By Danila Valmori,^* Uzi Gileadi, Catherine Servis,^§ P. Rod Dunbar, Jean-Charles Cerottini,^* Pedro Romero,^* Vincenzo Cerundolo, and Frédéric Lévy^*

From the ^* Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CH-1066 Epalinges, Switzerland; the  Institute of Molecular Medicine, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom; and the ^§ Institute of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland

We have analyzed the presentation of human histocompatability leukocyte antigen-A*0201-associated tumor peptide antigen MAGE-3_271-279 by melanoma cells. We show that specific cytotoxic T lymphocyte (CTL)-recognizing cells transfected with a minigene encoding the preprocessed fragment MAGE-3_271-279 failed to recognize cells expressing the full length MAGE-3 protein. Digestion of synthetic peptides extended at the NH₂ or COOH terminus of MAGE-3_271-279 with purified human proteasome revealed that the generation of the COOH terminus of the antigenic peptide was impaired. Surprisingly, addition of lactacystin to purified proteasome, though partially inhibitory, resulted in the generation of the antigenic peptide. Furthermore, treatment of melanoma cells expressing the MAGE-3 protein with lactacystin resulted in efficient lysis by MAGE-3_271-279-specific CTL. We therefore postulate that the generation of antigenic peptides by the proteasome in cells can be modulated by the selective inhibition of certain of its enzymatic activities.

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