Mutual antagonism of TGF-beta and Interleukin-2 in cell survival and lineage commitment of induced regulatory T cells

Cell Death Differ. 2012 Aug;19(8):1277-87. doi: 10.1038/cdd.2012.7. Epub 2012 Feb 10.


Transforming growth factor beta (TGF-β)- and Interleukin-2 (IL-2)-mediated signaling enables the generation and expansion of induced regulatory T (iTreg) cells that carry high hopes for the treatment of chronic inflammatory and autoimmune diseases. Knowledge about factors stabilizing their lineage commitment and lifespan, however, is limited. Here, we investigated the behavior of iTreg cells, derived from apoptosis-defective mouse mutants, during activated cell autonomous cell death, triggered by cytokine-deprivation, or activation-induced cell death (AICD) after restimulation of the T-cell receptor, and compared these responses with those of effector T cells. We observed that iTreg cells were much more sensitive to IL-2-deprivation but poorly susceptible to AICD. In fact, when apoptosis was compromised, T-cell receptor (TCR)-religation resulted in methylation-independent, ERK- and PI3K/mTOR-mediated loss of Foxp3 expression, impaired suppressive capacity and effector cytokine production. Although iTreg cells prevented colitis induction they rapidly lost Foxp3-GFP expression and gained ability to produce effector cytokines thereby imposing Th1 cell fate on resident effector cells. Surprisingly, iTreg cell conversion itself was limited by TGF-β-mediated Bim/Bcl2L11-dependent apoptosis. Hence, the very same cytokine that drives the generation of iTreg cells can trigger their demise. Our results provide novel insights in iTreg cell biology that will assist optimization of iTreg-based therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Cell Survival / immunology
  • Colitis / immunology
  • Fas Ligand Protein / immunology
  • Forkhead Transcription Factors / biosynthesis
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Interleukin-2 / immunology*
  • Interleukin-2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / immunology
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / immunology
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transforming Growth Factor beta / immunology*
  • Transforming Growth Factor beta / metabolism
  • fas Receptor / deficiency
  • fas Receptor / immunology


  • Bax protein (53-86)
  • Fas Ligand Protein
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Transforming Growth Factor beta
  • fas Receptor