ALTERED PEPTIDASE AND VIRAL-SPECIFIC T-CELL RESPONSE IN LMP2 MUTANT MICE

MHC class I molecules present peptides generated by processing of endo genously synthesized proteins to CD8(+) T lymphocytes. Recently, large proteolytic complexes, termed proteasomes, were implicated in antigen processing.Two proteasomal subunits, LMP2 and LMP7, are encoded withi n the MHC class II region, but their precise role in antigen processin g is unknown. We have generated mice that harbor a disruption in their LMP2 gene. Proteasomes purified from spleen and liver of these mutant mice exhibit altered peptidase activities, and antigen-presenting cel ls showed reduced capacity to stimulate a T cell hybridoma specific fo r H-2D(b) plus a nucleoprotein epitope of an influenza A virus. The mu tant mice have reduced (60%-70% of wild type) levels of CD8(+) T lymph ocytes and generate 5- to B-fold fewer influenza nucleoprotein-specifi c cytotoxic T lymphocyte precursors. These findings indicate that LMPS influences antigen processing.