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Foxp3+ T-regulatory cells require DNA methyltransferase 1 expression to prevent development of lethal autoimmunity

Liqing Wang1, Yujie Liu, Ulf H Beier

  • 1Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Blood
|February 28, 2013
PubMed

Insights

DNA methyltransferase 1 (Dnmt1) is crucial for maintaining T-regulatory (Treg) cell function and development. Its deletion in Tregs leads to lethal autoimmunity, cautioning against DNMT inhibitors in Treg cellular therapies.

Area of Science:

  • Immunology
  • Epigenetics
  • Cellular Therapy

Background:

  • Foxp3+ T-regulatory (Treg) cells are vital for immune homeostasis and are being explored for cellular therapies, particularly after allogeneic stem cell transplantation.
  • DNA methyltransferase (Dnmt) inhibitors are proposed to enhance Foxp3 expression in Tregs during in vitro expansion for therapeutic use.

Purpose of the Study:

  • To investigate the role of Dnmt1 and Dnmt3a in Treg development and function by examining the effects of their conditional deletion within Treg isolates.
  • To assess the impact of Dnmt1 deletion on Treg stability, gene expression, and the potential for autoimmunity.

Main Methods:

  • Conditional deletion of Dnmt1 and Dnmt3a enzymes in Treg isolates.
  • Analysis of peripheral Treg numbers and function.
  • Assessment of conventional T cell conversion into Foxp3+ Tregs.
  • Evaluation of methylation status at Foxp3 CpG sites and global DNA methylation.
  • Gene expression profiling of Tregs with conditional Dnmt1 deletion.
  • In vivo studies using mice with conditional Dnmt1 deletion in Tregs, including rescue experiments with wild-type Tregs.

Main Results:

  • Conditional deletion of Dnmt1, but not Dnmt3a, in Tregs reduced peripheral Treg numbers and function.
  • Dnmt1 deletion impaired the conversion of conventional T cells into Foxp3+ Tregs.
  • Mice with Dnmt1-deficient Tregs developed lethal autoimmunity unless rescued by wild-type Treg transplantation.
  • Dnmt1 deletion decreased global DNA methylation and altered the expression of numerous genes in Tregs, without affecting methylation within the Foxp3 gene locus.

Conclusions:

  • Dnmt1 is essential for maintaining the core gene program underlying Treg development and function.
  • Loss of Dnmt1 in the Treg lineage results in impaired Treg stability and function, leading to lethal autoimmunity.
  • Caution is advised when considering DNMT inhibitors for Treg-based cellular therapies due to potential adverse effects on Treg stability and function.

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