ollowing antigen exposure, mature lymphocytes require intense, prolonged and repeated proliferation to establish a rapid immune response and generate immunological memory. Proliferation also precedes induction of tolerance to soluble antigens. In addition, immune cells in bone marrow or thymus undergo repeated cycling as part of their development. It therefore appears that cell proliferation is a mandatory process for immune-system function. It has been established that deregulation of apoptosis in lymphocytes might lead to autoimmunity; this is the case for mice with defects in tumor necrosis factor (TNF) family apoptosis-related molecules such as the Fas/Fas signaling ligand system 1 , as well as in Bcl-2-overexpressing 2 or Bim-deficient mice 3 . Although Fas-defective CD4 Ϫ CD8 Ϫ T cells from MRL-lpr mice (a mouse substrain genetically predisposed to the development of systemic lupus erythematosus-like syndrome, which carries a mutation in the Fas gene) are unresponsive following in vitro stimulation 4 , we have shown that, in vivo, the T cells of young MRL-lpr mice overproliferate, suggesting that defective apoptosis might lead to increased cell cycling 5,6 . Increased lymphocyte cycling leads to break of tolerance and autoimmunity as well as lymphoma generation 7 . Defective apoptosis, especially in conjunction with cell-cycle defects, can also lead to development of lymphomas 8,9 . Loss of tolerance and autoimmunity might thus stem from apoptosis and/or cell division defects that are also characteristic of transformation.
Studies of mice deficient in various cell-cycle regulators have shown that some of these molecules are indispensable for cell-cycle control, others might be redundant, and the requirement for growth regulators might in some cases be tissue-specific 10,11 . We and others have recently reported that regulatory T-cell functions such as anergy and tolerance appear to be dependent on cell-cycle-related molecules not required for general cell-cycle control. On the basis of these findings and the prolific lymphocyte cycling observed during the immune response, we argue for a unique role for cell-cycle regulators in controlling lymphocyte proliferation, anergy and tolerance.
Cell-cycle regulation and the immune system
Following mitogenic stimulation, quiescent cells (G0 state) progress through the four cell-cycle phases: G1, the first gap phase, S, DNA synthesis, G2, the second gap phase, and M, mitosis. Control of this process is complex, involving a large number of positive regulators such as cyclins and cyclin-dependent kinases (CDK), and negative regulators such as CDK inhibitors. These events are described below (for review, see Refs 10-12) and outlined in a simplified scheme (Fig. 1). During G1/S phase progression, cyclins D (D1-D3) act in mid-G1, followed by cyclin E and cyclin A involved at the G1/S boundary; cyclins A and B act during S and G2/M phases. CDKs require association with cyclins as well as phosphorylation for activity. CDK4 and CDK6 are associated with cyclins D, whereas cyclins A and E assemble with CDK2. The activity of cyclin-CDK complexes is repressed by CDK inhibitors, which constrain entry into S phase. On the basis of their structural characteristics and CDK targets, two classes of CDK inhibitors have been defined. p15, p16, p18 and p19 are defined as INK4 (inhibitors of CDK4) and associate solely with CDK4 and CDK6. The other group of inhibitors includes p21, p27 and p57 (the Cip/Kip family), which interfere with cycling by binding to both cyclin and CDK subunits and inhibit all CDKs involved in G1/S transition. p21 and p27 contribute to the association and activation of cyclins D with their complementary CDK, indicating that these regulators also play a positive role in controlling G1/S transition 13 . Here, we present an abbreviated outline of cell-cycle control, but this is a rather complex process that involves other important regulators including, among others, the retinoblastoma tumor suppressor protein (Rb), which acts at several control points, or the p53 protein [10][11][12] .