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 G(0) to S phase, It was necessary to optimize the progress from the G(1)/S boundary to the G(2)/M phase, but not for the progress from the G(2)/M phase to the next G(1) 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 LAG. Mechanistically, we have found that cyclin-dependent kinase-2 (CDK2) and the cyclin E-associated kinase (largely CDK2), but not CDK4, in the G(1) phase were strongly inhibited by LAG. This could be an important mechanism for the proteasome to regulate the cell cycle, The degradation of cyclin E in the late G(1) 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 p27(Kip1) in the late G(1) phase when the proteasome activity was suppressed, and this might be a contributing mechanism for the observed inhibition of: CDK2 activity, Interestingly, p21(Cip1) was up-regulated during the G(1) phase, and the up-regulation was inhibited by LAG. 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.