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Role of Proteasomes in T Cell Activation and Proliferation¹

Xin Wang^*, Hongyu Luo^*, Huifang Chen^*, William Duguid and Jiangping Wu^2,*,,§

^* Laboratory of Transplantation Immunology, Louis-Charles Simard Research Center, and Nephrology Service, Notre-Dame Hospital, University of Montreal; and Montreal General Hospital and ^§ Department of Surgery, McGill University, Montreal, Canada

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 p27^Kip1 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, p21^Cip1 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.

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