ADAR1 Regulates Early T Cell Development via MDA5-Dependent and -Independent Pathways

ADAR1 is an RNA-editing enzyme that is abundant in the thymus. We have previously reported that ADAR1 is required for establishing central tolerance during the late stage of thymocyte development by preventing MDA5 sensing of endogenous dsRNA as nonself. However, the role of ADAR1 during the early developmental stage remains unknown. In this study, we demonstrate that early thymocyte-specific deletion of ADAR1 in mice caused severe thymic atrophy with excessive apoptosis and impaired transition to a late stage of development accompanied by the loss of TCR expression. Concurrent MDA5 deletion ameliorated apoptosis but did not restore impaired transition and TCR expression. In addition, forced TCR expression was insufficient to restore the transition. However, simultaneous TCR expression and MDA5 deletion efficiently ameliorated the impaired transition of ADAR1-deficient thymocytes to the late stage. These findings indicate that RNA-editing-dependent and -independent functions of ADAR1 synergistically regulate early thymocyte development.