TRANSCRIPTION FACTOR E2F CONTROLS THE REVERSIBLE GAMMA-DELTA T-CELL GROWTH ARREST MEDIATED THROUGH WC1

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 G(1) phase, We have previously shown that a gamma delta T cell- specific surface receptor, WC1, induces G(0)/G(1) growth arrest, rever sible with Con A, in proliferating IL-2-dependent gamma delta T cells. We now show that this reversible WC1-induced cell cycle arrest is cor related with induction of the cyclin kinase inhibitor p27kip1 and an a ssociated down-regulation in cyclins A, D2, and D3 expression, along w ith dephosphorylation of pocket proteins p107, p130, and pRb, Together with diminished pocket protein phosphorylation, p107 expression level s are significantly down-regulated in response to WC1 stimulation. Thi s coordinated sequence of signaling events is focused on E2F regulatio n 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. Consis tent with this interpretation, overexpression of E2F1 overcomes the gr owth-arresting effects induced by WC1 stimulation. Finally, in accorda nce with our previous observations at both the cellular and molecular level, subsequent mitogen stimulation can reverse all the above change s induced by WC1, These results, focused on E2F regulation, therefore provide a first insight into the effects of both positive (mitogen) an d negative (anti-WC1) stimuli on cell cycle control in IL-2-dependent gamma delta T cells.