RNA adenosine deaminase ADAR2 modulates T helper 17 cell effector function

Adenosine deaminases acting on RNA (ADARs) catalyze the most common RNA modification in mammals, but it remains to be elucidated how their RNA editing dependent and independent activities contribute to host immunity. Here, we report dynamic changes in ADARs expressions and global adenosine-to-inosin (A-to-I) editome during T helper cell differentiation. In differentiated T helper 17 (Th17) cells, transcription of the ADAR2 encoding locus is potentiated by an intragenic super enhancer and splicing of the ADAR2 encoding transcript is further facilitated by a DEAD-box RNA helicase, DDX5. In an editing-independent manner, ADAR2 negatively regulates Hypoxia-Inducible Factor 1-alpha (HIF1alpha) expression to limit the production of interleukin-10 (IL-10) in Th17 cells. These results demonstrate ADAR2 and the upstream mechanisms governing its expression as critical regulators of Th17 cell effector function.