Jennifer A. Stableford

Human Liver Dendritic Cells Promote T Cell Hyporesponsiveness

The liver is believed to promote tolerance, which may be beneficial due to its constant exposure to foreign Ags from the portal circulation. Although dendritic cells (DCs) are critical mediators of immune responses, little is known about human liver DCs. We compared freshly purified liver DCs from surgical specimens with autologous blood DCs. Liver and blood DCs were equally immature, but had distinct subset compositions. BDCA-1+ DCs represented the most prevalent liver DC subset, whereas the majority of peripheral blood DCs were CD16+. Upon TLR4 ligation, blood DCs secreted multiple proinflammatory cytokines, whereas liver DCs produced substantial amounts of IL-10. Liver DCs induced less proliferation of allogeneic T cells both in a primary MLR and after restimulation. Similarly, Ag-specific CD4+ T cells were less responsive to restimulation when initially stimulated by autologous liver DCs rather than blood DCs. In addition, liver DCs generated more suppressive CD4+CD25+FoxP3+ T regulatory cells and IL-4-producing Th2 cells via an IL-10-dependent mechanism. Our findings are critical to understanding hepatic immunity and demonstrate that human liver DCs promote immunologic hyporesponsiveness that may contribute to hepatic tolerance.

Dendritic cells are required for effective cross-presentation in the murine liver.

The liver harbors a diversity of cell types that have been reported to stimulate T cells. Although most hepatic dendritic cells are immature, a small population of CD11chigh conventional dendritic cells (cDCs) exists that expresses high levels of costimulatory molecules. We sought to determine the relative contribution of cDCs to cross‐presentation by the liver. In vitro, liver nonparenchymal cells (NPCs) depleted of cDCs induced only minimal proliferation and activation of antigen‐specific CD8+ T cells when loaded with soluble protein antigen. Using a transgenic mouse with the CD11c promoter driving expression of the human diphtheria toxin receptor, we found that selective depletion of cDCs in vivo reduced the number and activation of antigen‐specific CD8+ T cells in the liver after intravenous administration of soluble protein antigen. Adoptive transfer of DCs, but not CD40 stimulation, restored the hepatic T‐cell response. Conclusion: Our findings indicate that the ability of the liver to effectively cross‐present soluble protein to antigen‐specific CD8+ T cells depends primarily on cDCs. Despite costimulation, other resident liver antigen‐presenting cells cannot compensate for the absence of cDCs. (HEPATOLOGY 2008.)

Circulating HLA-DR+ natural killer cells have potent lytic ability and weak antigen-presenting cell function

Whether a freshly isolated immune cell can be equipped with both natural killing and antigen-presenting cell (APC) function has recently become controversial in mice. We sought to probe the existence of a candidate human cell with these properties by searching for cells in healthy subjects that co-express APC surface molecules and NK cell receptors. We have found that CD3(-)CD14(-)CD19(-) mononuclear cells of human blood, spleen, liver, and lymph nodes contain two distinct populations of cells that co-express HLA-DR (DR) and CD56. Circulating CD56(+) cells expressing high levels of DR were phenotypically and functionally similar to conventional CD56(-)dendritic cells (DC). Furthermore, we demonstrate here that a separate cohort of CD56(+) cells that express low levels of DR are NK cells that possess dual function as potent killers endowed with weak APC function.