p27kip1 inhibits systemic autoimmunity through the control of regulatory T cell activity and differentiation. p27kip1 inhibits systemic autoimmunity through the control of regulatory T cell activity and differentiation. M. Iglesias, J. Postigo, I. Santiuste, J. González, L. Buelta, E. Tamayo, J. Merino and R. Merino. 2012-11-01T23:00:00Z<p>​<strong class="ms-rteFontSize-2" style="text-align:justify;">Abstract:</strong></p><p style="text-align:justify;"><span class="ms-rteFontSize-2"><em>Objective.</em><em> </em>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 p27<sup>Kip1</sup>(p27) was involved in T cell anergy, we undertook this study to explore its role in both Treg cell processes.</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2"><em>Methods.</em><em> </em>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.</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2">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<sup>+</sup>cells was compared between these strains of mice.</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2"><em>Results.</em><em> </em>BCL2-TgT mice were protected against CIA by a Treg cell–dependent mechanism. In association with this protection, the overexpression of Bcl-2 in</span></p><p style="text-align:justify;"><span class="ms-rteFontSize-2">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.</span></p><p style="text-align:justify;"><em class="ms-rteFontSize-2">Conclusion.</em><em class="ms-rteFontSize-2"> </em><span class="ms-rteFontSize-2">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.</span><br></p><p><span class="ms-rteFontSize-2"></span></p><p><span class="ms-rteFontSize-2"><a href="https://onlinelibrary.wiley.com/doi/full/10.1002/art.37778">​Arthritis Rheum. 2013, 65: 343-354. DOI: 10.1002/art.37778.</a></span></p>160