The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

J Exp Med. 2008 Mar 17;205(3):565-74. doi: 10.1084/jem.20071477. Epub 2008 Feb 18.

Abstract

CD4(+)Foxp3(+) regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4(+) T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially diminished TGF-beta-induced Foxp3 expression in a kinase-dependent manner and via a rapamycin-sensitive pathway, implicating the AKT-mammalian target of rapamycin axis. The observed impairment in Foxp3 induction was part of a broad dampening of the typical T reg transcriptional signature. Expression of active AKT at a stage before Foxp3 turn on during normal T reg differentiation in the thymus selectively impaired differentiation of CD4(+)Foxp3(+) cells without any alteration in the positive selection of Tconv. Activated AKT, in contrast, did not affect established Foxp3 expression in T reg cells. These results place AKT at a nexus of signaling pathways whose proper activation has a strong and broad impact on the onset of T reg specification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Profiling
  • Immune Tolerance
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Oligonucleotide Array Sequence Analysis
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • TOR Serine-Threonine Kinases
  • Transduction, Genetic

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt

Associated data

  • GEO/GSE7596