ViewpointCell-cycle regulation in immunity, tolerance and autoimmunity
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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., 11., 12.) and outlined in a simplified scheme (Fig. 1). During
Control of anergy, tolerance and autoimmunity by cell-cycle regulators
In addition to their involvement in cell-cycle progression, some cell-cycle regulators control mechanisms implicated in T-cell tolerance, such as anergy. As mentioned above, p27 is associated with T-cell unresponsiveness; recent work shows that, following anergy induction via non-productive activation of T cells in the absence of costimulation, p27 accumulates in anergic lymphocytes26. In these experiments, a direct relationship between p27 and T-cell unresponsiveness was clearly documented in
Model of tolerance regulation by cell-cycle inhibitors
Although p21 and p27 participate in tolerance induction, the mechanism by which these molecules bring about unresponsiveness to self antigens is not clear. We propose a model that incorporates these two cell-cycle inhibitors in the sequence of events thought to result in T-cell tolerance, or break of tolerance and autoimmunity (Fig. 2).
Productive T-cell stimulation in vivo requires an inflammatory environment that elicits costimulatory interactions from antigen-presenting cells (APC); together
Concluding remarks
Here, we have analysed the relationship between cell-cycle regulation in T cells and specific immune functions, with particular focus on the role of p27 and p21 in T-cell anergy, tolerance and autoimmunity. Based on these data and the special proliferative characteristics of the immune system, we consider that cell-cycle regulators have a unique effect in controlling certain immune functions. This connection between immunity and cell-cycle regulation constitutes an exciting new area of
Acknowledgements
We would like to thank Marı́a Isabel Garcı́a for help with graphics and Catherine Mark for editorial assistance. The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (CSIC) and the Pharmacia Corporation.
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