Dual Function of IRF1/IRF4 on Dendritic Cells During Mouse Liver Transplantation

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Tolerogenic dendritic cells play an essential role in transplant tolerance induction. However, how to induce tolerogenic dendritic cells is not fully understood. Here, we sorted the IL10hi, IL10lo and IL10- dendritic cells using IL-10-Thy1.1 reporter mice. RNA-seq results showed that IRF1 was highly expressed, and IRF4 was low expressed in IL10hi dendritic cells. To better understand the function of IRF1/IRF4 on dendritic cells, we generated IRF1ko and IRF4ko bone marrow derived dendritic cells(BM-DC), and performed the BM-DC adoptive transfer induce tolerance experiment in the mouse liver transplantation models and found that IRF1ko BM-DC could induce transplant rejection and IRF4ko BM-DC could induce transplant tolerance. In vitro, IRF1ko BM-DC expressed higher amounts of CD80, CD86 and MHC class II and secreted less IL-27 and IL-10 as checked by ELISA after 100ng/ml LPS stimulation. Moreover, they could induce T cells to express more IFN-γbut less IL-10 in a co-culture experiment. But IRF4ko BM-DC has the opposite results. At last, we found that IRF1 could induce IL-27 and IL-10 expression, and it could be inhibit by IRF4 as determined by a Luciferase Reporter Assay. The bindings of IRF1 to IL-27 and IL-10 promoter were reduced in IRF4KO BM-DC as we found using Chip-PCR. Based on our findings, IRF1 and IRF4 have opposite function on dendritic cells, thus providing new possibilities for manipulation of dendritic cells during liver transplant tolerance induction.

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