Zhou, Q.; Wang, B.; Li, S.; Greasley, A.; Min, W.; Vareki, S. M.; Zheng, X.

Dendritic cells (DCs) are the main antigen-presenting cells and play a central role in activating adaptive immunity. How DCs is regulated during their development remains to be further elucidated. Circular RNA (circRNA) is a new type of non-coding RNA playing a critical in various cell events. However, little is known about the role of circRNA in DCs. Using in situ RNA hybridization, we found that DCs expressed exonic circular RNA AEBP2 (circAEBP2). circAEBP2 was upregulated in mature DCs compared to immature DCs. Knockdown of circAEBP2 in DCs using small interference RNA (siRNA) arrested DCs at an immature state with lower expression of MHC class II, CD40, CD80, and CD83. circAEBP2 knockdown in DCs also decreased the phosphorylation of nuclear factor-kappa B p65 (P-p65) but increased CD200R1. CircAEBP2-silenced DCs had a lower capacity to activate allogeneic CD4+ and CD8+ T cells in vitro and induced differentiation of regulatory T cells (Tregs). RNA immunoprecipitation assays revealed that circAEBP2 interacts with heterogeneous nuclear ribonucleoprotein F (hnRNP F) which is highly expressed in DCs and subsequently prevented hnRNP F nuclear translocation. In conclusion, we demonstrate that circAEBP2 regulates the development and function of DCs and knockdown of circAEBP2 induces tolerogenic DCs (Tol-DCs) through interacting with the hnRNP F/CD200R1/P-p65 signaling pathway. circAEBP2 is a new regulator in DCs and modulating it provides a novel strategy for inducing Tol-DCs.