title: Cutting Edge: Differential Regulation of PTEN by TCR, Akt, and FoxO1 Controls CD4+ T Cell Fate Decisions.
abstract: 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.
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors: William F
authors: WF
authors: Hawse
authors: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: Robert P
authors: RP
authors: Sheehan
authors: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: Natasa
authors: N
authors: Miskov-Zivanov
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors: Ashley V
authors: AV
authors: Menk
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and.
authors: Lawrence P
authors: http://orcid.org/0000-0001-5198-516X
authors: LP
authors: Kane
authors: Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.
authors: James R
authors: JR
authors: Faeder
authors: Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261; and morel@pitt.edu.
authors: Penelope A
authors: PA
authors: Morel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology*; D055785:Gene Knockdown Techniques; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008962:Models, Theoretical; D051058:Oncogene Protein v-akt / Q000276:immunology*; D051059:PTEN Phosphohydrolase / Q000276:immunology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse