Signaling via the Akt/mammalian target of rapamycin pathway influences CD4+ T cell differentiation; low levels favor regulatory T cell induction and high levels favor Th induction. Although the lipid phosphatase phosphatase and tensin homolog (PTEN) suppresses Akt activity, the control of PTEN activity is poorly studied in T cells. In this study, we identify multiple mechanisms that regulate PTEN expression. During Th induction, PTEN function is suppressed via lower mRNA levels, lower protein levels, and an increase in C-terminal phosphorylation. Conversely, during regulatory T cell induction, PTEN function is maintained through the stabilization of PTEN mRNA transcription and sustained protein levels. We demonstrate that differential Akt/mammalian target of rapamycin signaling regulates PTEN transcription via the FoxO1 transcription factor. A mathematical model that includes multiple modes of PTEN regulation recapitulates our experimental findings and demonstrates how several feedback loops determine differentiation outcomes. Collectively, this work provides novel mechanistic insights into how differential regulation of PTEN controls alternate CD4+ T cell fate outcomes.
This work was supported by National Institutes of Health Grant P41 GM103712 and National Science Foundation Grant 0926181 (to J.R.F. and N.M.-Z.), National Institutes of Health Grants GM080398 and AI095730 (to L.P.K.), and by National Institutes of Health Postdoctoral Training Grant T32 AI089443 (to W.F.H.) and Predoctoral Training Grant T32 EB009403 (to R.P.S.).
The online version of the article contains supplemental material.
- Received October 16, 2014.
- Accepted March 12, 2015.
- Copyright © 2015 by The American Association of Immunologists, Inc.