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Mechanistic Insights into Impaired Dendritic Cell Function by Rapamycin: Inhibition of Jak2/Stat4 Signaling Pathway¹

Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15261

The suppressive effect of rapamycin on T cells has been extensively studied, but its influence on the function of APC is less clear. The data in this study demonstrated that immunostimulatory activity of B10 (H2^b) dendritic cells (DC) exposed to rapamycin (rapa-DC) was markedly suppressed as evidenced by the induction of low proliferative responses and specific CTL activity in allogeneic (C3H, H2^k) T cells. Administration of rapa-DC significantly prolonged survival of B10 cardiac allografts in C3H recipients. Treatment with rapamycin did not affect DC expression of MHC class II and costimulatory molecules or IL-12 production. Rapamycin did not inhibit DC NF-B pathway, however, IL-12 signaling through Janus kinase 2/Stat4 activation was markedly suppressed. Indeed, Stat4^-/- DC similarly displayed poor allostimulatory activity. The Stat4 downstream product, IFN-, was also inhibited by rapamycin, but DC dysfunction could not solely be attributed to low IFN- production as DC deficient in IFN- still exhibited vigorous allostimulatory activity. Rapamycin did not affect DC IL-12R expression, but markedly suppressed IL-18R and expression, which may in turn down-regulate DC IL-12 autocrine activation.

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