Development of the reconstituted antigen presenting system and its medical application

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The proteasome, a large multisubunit cimplex, has been implicated to be a processing enzyme of endogeneous antigens, which is involved in the recognition between self and non-self in the adaptive immunity, implying that it plays an indispensable role for triggering the cell-mediated immunity. We found that interferon-gamma (IFN-gamma) induces subunit replacement of three pair of proteasomal subunits with high homology, producing "immunoproteasomes" termed to emphasize their specialized functions for antigen procesisng, indicating that the antigen processing process can be regulated in response to various extracellular signals. Analysis of genetic loci of the genes encoding IFN-gamma responsible proteasomal subunits revealed that various genes located on the MHC regions, such as TAP (transporter associated with antigen processing) and immunoproteasomal LMP2/LMP7 subunits have been produced by an ancient chromosomal duplication, providing a new hypothesis for the origin of the MHC genes. In addition, we found that a novel proteasomal activator protein PA28, consisting of three homologous family proteins, also are regulated by IFN-gamma, indicating that PA28 plays an essential role for the immune response. Finally, we found that the proteasome can generate antigenic peptide in vitro from the synthetic precursor plypeptide covering the CTL epitopic sequences by recognizing strictly the length and sequence of the targe polypeptides Moreover, PA28 was found to collaborate with the proteasome to excise correctly antigenic peptide in a dual-cleavage fashion. These observations provide a new insight for our understanding of the regulatory mechanisms of processing and presentation of endogenous antigens. These findings would contribute to developement of the reconstituted antigen presenting system in vitro.