Role of proteasomes in T cell activation and proliferation.

The role of proteasomes in T cell activation, proliferation, and apoptosis was investigated using a proteasome-specific inhibitor lactacystin (LAC). Inhibition of the proteasome activity by LAC repressed the mitogen-induced T cell proliferation. The proteasome activity was definitively required for the T cells to progress from the G0 to S phase. It was necessary to optimize the progress from the G1/S boundary to the G2/M phase, but not for the progress from the G2/M phase to the next G1 phase. Probably as a result of a blockage of cell cycle progress, the cycling, but not the resting, T cells underwent apoptosis when treated with LAC. Mechanistically, we have found that cyclin-dependent kinase-2 (CDK2) and the cyclin E-associated kinase (largely CDK2), but not CDK4, in the G1 phase were strongly inhibited by LAC. This could be an important mechanism for the proteasome to regulate the cell cycle. The degradation of cyclin E in the late G1 and early S phases was dependent on the proteasome, although it was unlikely that this accounted for the observed inhibition of T cell proliferation. There was a reduced decay of p27Kip1 in the late G1 phase when the proteasome activity was suppressed, and this might be a contributing mechanism for the observed inhibition of CDK2 activity. Interestingly, p21Cip1 was up-regulated during the G1 phase, and the up-regulation was inhibited by LAC. Our study shows that the proteasome plays pivotal roles in regulating T cell activation and proliferation, and its effect is probably exerted through multiple mechanisms.