title: IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells.
abstract: Plasmacytoid dendritic cells (pDCs) are highly specialized APCs that, in addition to their well-recognized role in anti-viral immunity, also regulate immune responses. Liver-resident pDCs are considerably less immunostimulatory than those from secondary lymphoid tissues and are equipped to promote immune tolerance/regulation through various mechanisms. IL-27 is an IL-12 family cytokine that regulates the function of both APCs and T cells, although little is known about its role in pDC immunobiology. In this study, we show that mouse liver pDCs express higher levels of IL-27p28 and EBV-induced protein 3 (Ebi3) compared with those of splenic pDCs. Both populations of pDCs express the IL-27Rα/WSX-1; however, only liver pDCs significantly upregulate expression of the coregulatory molecule B7 homolog-1 (B7-H1) in response to IL-27. Inhibition of STAT3 activation completely abrogates IL-27-induced upregulation of B7-H1 expression on liver pDCs. Liver pDCs treated with IL-27 increase the percentage of CD4(+)Foxp3(+) T cells in MLR, which is dependent upon expression of B7-H1. pDCs from Ebi3-deficient mice lacking functional IL-27 show increased capacity to stimulate allogeneic T cell proliferation and IFN-γ production in MLR. Liver but not spleen pDCs suppress delayed-type hypersensitivity responses to OVA, an effect that is lost with Ebi3(-/-) and B7-H1(-/-) liver pDCs compared with wild-type liver pDCs. These data suggest that IL-27 signaling in pDCs promotes their immunoregulatory function and that IL-27 produced by pDCs contributes to their capacity to regulate immune responses in vitro and in vivo.
authors.affiliation: Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Matta
authors.forename: Giorgio
authors.initials: G
authors.lastname: Raimondi
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rosborough
authors.forename: Tina L
authors.initials: TL
authors.lastname: Sumpter
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000172:deficiency; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007378:Interleukins / Q000096:biosynthesis*; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D010047:Ovalbumin / Q000502:physiology; D018121:Receptors, Cytokine / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C499601:Ebi3 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D010047:Ovalbumin