p27Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation
Article first published online: 28 JAN 2013
Copyright © 2013 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 65, Issue 2, pages 343–354, February 2013
How to Cite
Iglesias, M., Postigo, J., Santiuste, I., González, J., Buelta, L., Tamayo, E., Merino, J. and Merino, R. (2013), p27Kip1 inhibits systemic autoimmunity through the control of Treg cell activity and differentiation. Arthritis & Rheumatism, 65: 343–354. doi: 10.1002/art.37778
- Issue published online: 28 JAN 2013
- Article first published online: 28 JAN 2013
- Accepted manuscript online: 2 NOV 2012 12:18PM EST
- Manuscript Accepted: 25 OCT 2012
- Manuscript Received: 28 FEB 2012
- Ministerio de Ciencia e Innovación, Spain. Grant Numbers: BFU2009-07206, SAF2011-22463
- European Regional Development Fund. Grant Number: SAF2008-02042
- Fundación Eugenio Rodríguez Pascual, Spain
- Fundación Marqués de Valdecilla-Leonardo Torres Quevedo, Spain. Grant Number: FMV-UC 08/02
Despite the importance of Treg cells in the maintenance of immunologic tolerance, the mechanisms that control their generation and activity are unknown. Since the cell cycle inhibitor p27Kip1 (p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes.
The development of type II collagen–induced arthritis (CIA) and lupus-like abnormalities was compared between transgenic mice overexpressing human Bcl-2 in T cells (BCL2-TgT mice) and nontransgenic mice that were deficient or not deficient in p27. The contribution of Treg cells to disease evolution was also explored. Finally, the in vitro activity of Treg cells and their differentiation from naive CD4+ cells was compared between these strains of mice.
BCL2-TgT mice were protected against CIA by a Treg cell–dependent mechanism. In association with this protection, the overexpression of Bcl-2 in T cells enhanced the differentiation and activity of Treg cells. Both Bcl-2 effects were independent of its antiapoptotic activity but dependent on its capacity to induce the expression of p27 that augmented the strength of transforming growth factor β (TGFβ) signaling in T cells. Accordingly, down-modulation of p27 expression in BCL2-TgT mice promoted CIA. In addition, p27 deficiency in aged C57BL/6 mice reduced the number and activity of Treg cells and induced the development of mild lupus-like abnormalities.
Our results point to p27 as a critical regulator of Treg cell differentiation and function through the positive modulation of TGFβ signaling strength in T cells.