A distal Foxp3 enhancer enables interleukin-2 dependent thymic Treg cell lineage commitment for robust immune tolerance

Immunity. 2021 May 11;54(5):931-946.e11. doi: 10.1016/j.immuni.2021.03.020. Epub 2021 Apr 9.


Activation of the STAT5 transcription factor downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic effects of IL-2R signaling, it is unclear how STAT5 acts directly on the Foxp3 locus to promote its expression. Here, we report that IL-2 - STAT5 signaling converged on an enhancer (CNS0) during Foxp3 induction. CNS0 facilitated the IL-2 dependent CD25+Foxp3- precursor to Treg cell transition in the thymus. Its deficiency resulted in impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS0 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS0 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms minimizes autoimmunity.

Keywords: Foxp3; Regulatory T cells; enhancer; immune tolerance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoimmunity / immunology
  • Cell Differentiation / immunology
  • Cell Lineage / immunology*
  • Enhancer Elements, Genetic / immunology
  • Female
  • Forkhead Transcription Factors / immunology*
  • Humans
  • Immune Tolerance / immunology*
  • Interleukin-2 / immunology*
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Male
  • Mice
  • Receptors, Interleukin-2 / immunology
  • STAT5 Transcription Factor / immunology
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Interleukin-2
  • STAT5 Transcription Factor