MiRNA-181a is critical for the tolerogenic properties of plasmacytoid dendritic cells (TRAN3P.886)

Abstract

Abstract Liver allografts are well tolerated and other solid organ allografts, when transplanted concurrently with livers, show improved graft outcomes. However, the mechanisms underlying “hepatic tolerance” have yet to be elucidated. Previous data show that hepatic dendritic cells (HDC) have diminished antigen presenting and immune stimulatory function compared with DC in lymphoid tissue. It has been hypothesized that immature plasmacytoid (p)DC are inherently tolerogenic with studies supporting this hypothesis. Our work confirms that HpDC prolong cardiac allograft survival (p<0.01) in a murine model compared to bulk and myeloid (m)DC. Micro-ribonucleic acid (miR) are short (15-22 nucleotides) RNA molecules which can post-transcriptionally regulate messenger RNA transcripts, resulting in translational repression or upregulation. We hypothesize that miR-181a, which we found is highly expressed in HpDC, plays a critical role in the tolerogenic properties of pDC. TLR 9 stimulation of pDC from miR-181a-/- mice exhibited higher levels of maturation markers and differential cytokine production as compared to wild-type C57BL/6 mice. More, there is altered phosphorylation of key members of signal transduction pathways, such as ERK1/2. Finally, in the same murine model of cardiac allograft transplantation, use of pDC from miR-181a-/- mice abrograted the tolerogenic properties seen with HpDC. Together, our data shows a critical role for miR-181a in the tolerance-inducing properties of pDC.