In situ conversion of defective Treg into SuperTreg cells to treat advanced IPEX-like disorders in mice

Nat Commun. 2020 Jun 3;11(1):2781. doi: 10.1038/s41467-020-15836-2.


Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear. Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg cell activation and causes fatal autoimmunity in mice. Here, we show with a reversible knockout model that re-expression of Brg1, in conjunction with the severe endogenous proinflammatory environment, can convert defective Treg cells into powerful, super-activated Treg cells (SuperTreg cells) that can resolve advanced autoimmunity, with Brg1 re-expression in a minor fraction of Treg cells sufficient for the resolution in some cases. SuperTreg cells have enhanced trafficking and regulatory capabilities, but become deactivated as the inflammation subsides, thus avoiding excessive immune suppression. We propose a simple, robust yet safe gene-editing-based therapy for IPEX and IPEX-related disorders that exploits the defective Treg cells and the inflammatory environment pre-existing in the patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cytokines / metabolism
  • DNA Helicases / deficiency
  • Diabetes Mellitus, Type 1 / congenital*
  • Diabetes Mellitus, Type 1 / immunology
  • Diarrhea / immunology*
  • Female
  • Gene Expression Regulation / drug effects
  • Genetic Diseases, X-Linked / immunology*
  • Green Fluorescent Proteins / metabolism
  • Immune System Diseases / congenital*
  • Immune System Diseases / immunology
  • Lymphocyte Activation / immunology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / deficiency
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, CXCR3 / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Survival Analysis
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Tamoxifen / pharmacology
  • Transcription Factors / deficiency


  • Cytokines
  • Nuclear Proteins
  • Receptors, CXCR3
  • STAT1 Transcription Factor
  • Transcription Factors
  • Tamoxifen
  • Green Fluorescent Proteins
  • Proto-Oncogene Proteins c-akt
  • Smarca4 protein, mouse
  • DNA Helicases

Supplementary concepts

  • Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome