The control of CD4+CD25+Foxp3+ regulatory T cell survival

Biol Direct. 2008 Feb 27;3:6. doi: 10.1186/1745-6150-3-6.

Abstract

CD4+CD25+Foxp3+ regulatory T (Treg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that Treg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of Treg cells in Bim-/- and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25+ cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in Treg cells. Our study reveals that the survival of Treg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate Treg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate Treg cells that could be utilized for their therapeutic applications.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Survival / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Forkhead Transcription Factors / biosynthesis*
  • Forkhead Transcription Factors / physiology
  • Homeostasis / immunology
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / physiology*
  • Interleukin-2 Receptor alpha Subunit / biosynthesis*
  • Interleukin-2 Receptor alpha Subunit / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, SCID
  • Mice, Transgenic
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-2 Receptor alpha Subunit