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Molecular and Cellular Biology, April 2003, p. 2351-2361, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2351-2361.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Commitment Point during G0->G1 That Controls Entry into the Cell Cycle

Nicholas C. Lea,1 Stephen J. Orr,1 Kai Stoeber,2 Gareth H. Williams,2 Eric W.-F. Lam,3 Mohammad A. A. Ibrahim,4 Ghulam J. Mufti,1 and N. Shaun B. Thomas1*

Departments of Haematological Medicine,1 Clinical Immunology, Leukaemia Sciences Laboratories, Guy's, King's and St. Thomas’ School of Medicine, London SE5 9NU, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT,4 ,2 Cancer Research UK Labs and Section of Cancer Cell Biology, Imperial College School of Medicine at Hammersmith Hospital, London W12 0NN, United Kingdom3

Received 23 August 2002/ Returned for modification 8 October 2002/ Accepted 16 January 2003

Initiation of T-lymphocyte-mediated immune responses involves two cellular processes: entry into the cell cycle (G0->G1) for clonal proliferation and coordinated changes in surface and secreted molecules that mediate effector functions. However, a point during G0->G1 beyond which T cells are committed to enter the cell cycle has not been defined. We define here a G0->G1 commitment point that occurs 3 to 5 h after CD3 and CD28 stimulation of human CD4 or CD8 T cells. Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16INK4A during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G0. Transition through the G0->G1 commitment point is also necessary for T cells to increase in size, i.e., to enter the cellular growth cycle. However, transition through this point is not required for the induction of effector functions. These can be initiated while cells are maintained in G0 with TAT-p16INK4A. We have termed this quiescent, activated state G0(A). Our data provide proof of the principle that entry of T cells into the cell cycle and cellular growth cycles are coupled at the G0->G1 commitment point but that these processes can be uncoupled from the early expression of molecules of effector functions.

* Corresponding author. Mailing address: Department of Haematological Medicine, Leukaemia Sciences Laboratories, Guy's, King's, and St. Thomas' School of Medicine, Rayne Institute, 123 Coldharbour La., London SE5 9NU, United Kingdom. Phone: 44-20-7848-5818. Fax: 44-20-7848-5814. E-mail: nicholas.s.thomas{at}kcl.ac.uk.

Molecular and Cellular Biology, April 2003, p. 2351-2361, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2351-2361.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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