ADAR 1‐mediated RNA editing is required for thymic self‐tolerance and inhibition of autoimmunity

T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 ( ADAR 1) is the enzyme responsible for adenosine‐to‐inosine RNA editing in ds RNA s, and loss of ADAR 1 activates the innate immune sensing response via melanoma differentiation‐associated protein 5 ( MDA 5), which interprets unedited ds RNA as non‐self. Although ADAR 1 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 ADAR 1‐deficient thymocytes. Intriguingly, concurrent deletion of MDA 5 restores thymocyte maturation and prevents colitis. These findings suggest that prevention of MDA 5 sensing of endogenous ds RNA by ADAR 1‐mediated RNA editing is required for preventing both innate immune responses and T cell‐mediated autoimmunity.