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

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Abstract

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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