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Cell-cycle regulation in immunity, tolerance and autoimmunity

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Abstract

To trigger an effective immune response, lymphocytes must proliferate. In addition to their direct involvement in cell-cycle progression, cell-cycle regulators might thus control immune functions. Recent evidence suggests that these regulators are essential for T-cell function; we argue that their study will provide clues for dissecting anergy and tolerance mechanisms, as well as for intervention in autoimmune diseases.

Section snippets

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.

References (41)

  • A. Tamir et al.

    Aging impairs induction of cyclin-dependent kinases down-regulation of p27 in mouse CD4+ cells

    Cell Immunol.

    (1999)
  • M.W. Mullins

    CD40-mediated induction of p21 accumulation in resting and cycling B cells

    Mol. Immunol.

    (1998)
  • J. Xaus

    Interferon g induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis

    Immunity

    (1999)
  • C. Deng

    Mice lacking p21CIP1/WAF-1 undergo normal development, but are defective in G1 checkpoint control

    Cell

    (1995)
  • M.K. Jenkins

    The ups and downs of T cell costimulation

    Immunity

    (1994)
  • P.S. Ohashi et al.

    Autoimmunity: a bias from tolerance to autoimmunity

    Curr. Opin. Immunol.

    (1997)
  • A. Strasser

    Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease

    Proc. Natl. Acad. Sci. U. S. A.

    (1991)
  • P. Bouillet

    Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity

    Science

    (1999)
  • D. Balomenos

    The proliferative in vivo activities of lpr double-negative T cells and the primary role of p59fyn in their activation and expansion

    J. Immunol.

    (1997)
  • D. Balomenos

    Interferon-γ is required for lupus-like disease and lymphoaccumulation

    J. Clin. Invest.

    (1998)
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