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 (HIF1) 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. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/308221v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@11f3918org.highwire.dtl.DTLVardef@dd8d99org.highwire.dtl.DTLVardef@17b6042org.highwire.dtl.DTLVardef@eca775_HPS_FORMAT_FIGEXP M_FIG C_FIG Major findings: Naive and Th17 cells harbored overlapping and unique A-to-I editome. ADAR2 expression is induced during Th17 polarization under the control of an intragenic super enhancer. ADAR2 targets Hif1a transcripts to regulate HIF1 expression and IL- 10 production in ROR{gamma}t+ Th17 cells in the small intestine. Post-transcriptionally, Adarb1 pre-mRNAs are bound and regulated by RNA binding DEAD-box protein DDX5. DDX5-deficient Th17 cells have a dysregulated RNA editome and altered effector function.