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.