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

Abstract 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.