Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation

Aryl hydrocarbon receptor (AHR) plays critical roles in various autoimmune diseases such as multiple sclerosis by controlling in-terleukin- 17 (IL-17)-producing T-helper (T(H)17) and regulatory T cells. Although various transcription factors and cytokines have been identified as key participants in TH17 generation, the role of microRNAs in this process is poorly understood. In this study, we found that expression of the microRNA (miR)-132/212 cluster is up-regulated by AHR activation under T(H)17-inducing, but not regulatory T-inducing conditions. Deficiency of the miR-132/212 cluster prevented the enhancement of T(H)17 differentiation by AHR activation. We also identified B-cell lymphoma 6, a negative regulator of T(H)17 differentiation, as a potential target of the miR-212. Finally, we investigated the roles of the miR-132/212 cluster in experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Mice deficient in the miR-132/212 cluster exhibited significantly higher resistance to the development of experimental autoimmune encephalomyelitis and lower frequencies of both T(H)1 and T(H)17 cells in draining lymph nodes. Our findings reveal a unique mechanism of AHR-dependent T(H)17 differentiation that depends on the miR-132/212 cluster.