Differential influence on cytotoxic T lymphocyte epitope presentation by controlled expression of either proteasome immunosubunits or PA28

The proteasome is the principal provider of major histocompatibility comple x (MHC) class I-presented peptides. Interferon (IFN)-gamma induces expressi on of three catalytically active proteasome subunits (LMP2, LMP7, and MECL- 1) and the proteasome-associated activator PA28. These molecules are though t to optimize the generation of MHC class I-presented peptides. However, kn own information on their contribution in vivo is very limited. Here, we exa mined the antigen processing of two murine leukemia virus-encoded cytotoxic T lymphocyte (CTL) epitopes in murine cell lines equipped with a tetracycl ine-controlled, IFN-gamma-independent expression system. We thus were able to segregate the role of the immunosubunits from the role of PA28. The pres ence of either immunosubunits or PA28 did not alter the presentation of a s ubdominant murine leukemia virus (MuLV)-derived CTL epitope. However, the p resentation of the immunodominant MuLV-derived epitope was markedly enhance d upon induction of each of these two sets of genes. Thus, the IFN-gamma-in ducible proteasome subunits and PA28 can independently enhance antigen pres entation of some CTL epitopes. Our data show that tetracycline-regulated ex pression of PA28 increases CTL epitope generation without affecting the 20S proteasome composition or half-life. The differential effect of these IFN- gamma-inducible proteins on MHC class I processing may have a decisive infl uence on the quality of the CTL immune response.