Date: Monday, May 1, 2017
Session Name: Concurrent Session: Regulatory Cells in Alloimmunity
Session Time: 4:30pm-6:00pm
Presentation Time: 4:42pm-4:54pm
We previously found that the cyclin-dependent kinase CDK2 phosphorylates the Treg transcription factor Foxp3, targeting it for proteolytic degradation. Treg with defective CDK2 activity express more Foxp3 and are better able to mediate cardiac allograft tolerance in response to costimulatory blockade. We now report that normal Treg development in the thymus and TGFB-mediated iTreg differentiation is associated with marked induction of p27kip1, the natural inhibitor of CDK2. This suggests that effective Treg development or function may require tight control of CDK activity. Indeed, conventional CD4+ T cells genetically deficient for p27kip1 exhibited defective induction of Foxp3 in response to TGFB in vitro, which was associated with CDK2-mediated phosphorylation of Foxp3 as measured by a novel phospho-specific Ab. To determine whether p27kip1 is required for Treg function in vivo, we used p27kip1-fl/fl-Foxp3-YFP-Cre mice in which p27kip1 is specifically deleted in the Treg lineage as recipients of cardiac allografts treated with CD28-CD40 costimulatory blockade. While this treatment led to long-term acceptance of cardiac allografts in p27kip1-sufficient control recipients, recipients with Treg-specific deletion of p27kip1 rejected their allografts. These studies establish a Treg-intrinsic role for p27kip1 in Treg stability and function, and point to the cyclin-dependent kinase pathway as a potential new therapeutic target for promoting transplantation tolerance.
CITATION INFORMATION: Morawski P, Wang L, Yang X, Chen Y, Hancock W, Wells A. A Regulatory T Cell (Treg)-Intrinsic Role for p27kip1 in Acquired Transplant Tolerance. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Morawski P, Wang L, Yang X, Chen Y, Hancock W, Wells A. A Regulatory T Cell (Treg)-Intrinsic Role for p27kip1 in Acquired Transplant Tolerance. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/a-regulatory-t-cell-treg-intrinsic-role-for-p27kip1-in-acquired-transplant-tolerance/. Accessed May 28, 2020.
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