ADAR1-mediated RNA editing is required for thymic self-tolerance and inhibition of autoimmunity

EMBO Rep. 2018 Dec;19(12):e46303. doi: 10.15252/embr.201846303. Epub 2018 Oct 25.


T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 (ADAR1) is the enzyme responsible for adenosine-to-inosine RNA editing in dsRNAs, and loss of ADAR1 activates the innate immune sensing response via melanoma differentiation-associated protein 5 (MDA5), which interprets unedited dsRNA as non-self. Although ADAR1 is highly expressed in the thymus, its role in the adaptive immune system, especially in T cells, remains elusive. Here, we demonstrate that T cell-specific deletion of Adar1 in mice causes abnormal thymic T cell maturation including impaired negative selection and autoimmunity such as spontaneous colitis. This is caused by excessive expression of interferon-stimulated genes, which reduces T cell receptor (TCR) signal transduction, due to a failure of RNA editing in ADAR1-deficient thymocytes. Intriguingly, concurrent deletion of MDA5 restores thymocyte maturation and prevents colitis. These findings suggest that prevention of MDA5 sensing of endogenous dsRNA by ADAR1-mediated RNA editing is required for preventing both innate immune responses and T cell-mediated autoimmunity.

Keywords: MDA5; RNA editing; T cell maturation; negative selection; spontaneous colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / deficiency
  • Adenosine Deaminase / metabolism*
  • Animals
  • Autoimmunity*
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / genetics
  • Colitis / immunology
  • Colitis / pathology
  • Gene Deletion
  • Inflammation / immunology
  • Inflammation / pathology
  • Interferon-Induced Helicase, IFIH1 / metabolism
  • Interferons / metabolism
  • Lymphocyte Activation / immunology
  • Mice, Knockout
  • RNA Editing*
  • Receptors, Antigen, T-Cell / metabolism
  • Self Tolerance*
  • Signal Transduction
  • Thymocytes / metabolism
  • Thymus Gland / metabolism*
  • Up-Regulation / genetics


  • Receptors, Antigen, T-Cell
  • Interferons
  • ADAR1 protein, mouse
  • Adenosine Deaminase
  • Ifih1 protein, mouse
  • Interferon-Induced Helicase, IFIH1