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Transcription Factor E2F Controls the Reversible T Cell Growth Arrest Mediated Through WC1¹

Paul A. Kirkham^2,*, Eric W.-F. Lam, Haru-Hisa Takamatsu^*, R. Michael^* and E. Parkhouse^*

^* Department of Immunology, Institute for Animal Health, Pirbright, Surrey, United Kingdom; and Ludwig Institute for Cancer Research and Department of Medical Microbiology, Imperial College School of Medicine at St Mary’s Hospital, London, United Kingdom

IL-2-stimulated expansion of T cells requires continued and sequential passage of the dividing cells through a major cell cycle check point in the G₁ phase. We have previously shown that a T cell-specific surface receptor, WC1, induces G₀/G₁ growth arrest, reversible with Con A, in proliferating IL-2-dependent T cells. We now show that this reversible WC1-induced cell cycle arrest is correlated with induction of the cyclin kinase inhibitor p27kip1 and an associated down-regulation in cyclins A, D2, and D3 expression, along with dephosphorylation of pocket proteins p107, p130, and pRb. Together with diminished pocket protein phosphorylation, p107 expression levels are significantly down-regulated in response to WC1 stimulation. This coordinated sequence of signaling events is focused on E2F regulation so that, downstream of the pocket proteins, WC1 stimulation results in a diminished DNA binding activity for free E2F as a consequence of reduced E2F1 expression, whereas E2F4 expression is unaffected. Consistent with this interpretation, overexpression of E2F1 overcomes the growth-arresting effects induced by WC1 stimulation. Finally, in accordance with our previous observations at both the cellular and molecular level, subsequent mitogen stimulation can reverse all the above changes induced by WC1. These results, focused on E2F regulation, therefore provide a first insight into the effects of both positive (mitogen) and negative (anti-WC1) stimuli on cell cycle control in IL-2-dependent T cells.

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