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Dendritic cells with METTL3 gene knockdown exhibit immature properties and prolong allograft survival

Abstract

Maturation of dendritic cells (DCs) initiates adaptive immune responses and thereby provokes allograft rejection. Here, this study aimed to explore the effect of Methyltransferase-like protein 3 (METTL3) silencing on DC function and the role of METTL3-silencing donor DCs in the immune response after mouse heart transplantation. Bone marrow-derived DCs from donor BALB/c mice were infected with lentiviruses expressing METTL3-specific short hairpin RNA (LV-METTL3 shRNA) to silence METTL3. Then METTL3-silencing DCs were treated with lipopolysaccharide (LPS) for another 48 h to induce DC maturation. Recipient C57BL/6 mice were injected with phosphate-buffered saline (PBS), immature DCs, and METTL3 shRNA-DCs prior to the cardiac transplantation involving the transfer of hearts from donor BALB/c mice to recipient C57BL/6 mice. In vitro we demonstrated that METTL3-silencing DCs had lower expression of MHCII, costimulatory molecules (CD80, CD86), and DC-related cytokines (IFN-γ, IL-12) as well as lower ability to activate T-cell proliferation, which were consistent with the characteristics of tolerogenic DCs. In vivo we found that METTL3-silencing donor DCs induced immune tolerance after mouse heart transplantation and prolonged the allograft survival, which might be associated with Th1/Th2 immune deviation. In summary, METTL3-silencing DCs exhibit immature properties and prolong allograft survival.

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Fig. 1: METTL3 was highly expressed in mDCs.
Fig. 2: METTL3 knockdown suppressed DC maturation.
Fig. 3: METTL3 knockdown suppressed allogeneic T-cell proliferation and regulated Th1/Th2 cell percentage.
Fig. 4: METTL3 knockdown induced immune tolerance in mouse heart transplantation.
Fig. 5: METTL3 knockdown prolonged the allograft survival.

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Correspondence to Zhiwei Wang.

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Wu, H., Xu, Z., Wang, Z. et al. Dendritic cells with METTL3 gene knockdown exhibit immature properties and prolong allograft survival. Genes Immun 21, 193–202 (2020). https://doi.org/10.1038/s41435-020-0099-3

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