The selective proteasome inhibitors lactacystin and epoxomicin can be usedto either up- or down-regulate antigen presentation at nontoxic doses

The complete inhibition of proteasome activities interferes with the produc tion of most MHC class I peptide ligands as well as with cellular prolifera tion and survival. In this study we have investigated how partial and selec tive inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentatio n, At 0.5-1 mu M lactacystin, the presentation of the Lymphocytic choriomen ingitis virus-derived epitopes NP118 and GP33 and the mouse CMV epitope pp8 9-168 were reduced and were further diminished in a dose-dependent manner w ith increasing concentrations. Presentation of the lymphocytic choriomening itis virus-derived epitope GP276, in contrast, was markedly enhanced at low , but abrogated at higher, concentrations of either lactacystin or epoxomic in, The inhibitor-mediated effects were thus epitope specific and did not c orrelate with the degradation rates of the involved viral proteins. Althoug h neither apoptosis induction nor interference with cellular proliferation was observed at 0.5-1 mu M lactacystin in vivo, this concentration was suff icient to alter the fragmentation of polypeptides by the 20S proteasome in vitro. Our results indicate that partial and selective inhibition of protea some activity in vivo is a valid approach to modulate Ag presentation, with potential applications for the treatment of autoimmune diseases and the pr evention of transplant rejection.