title: Tolerogenic effect of mouse fibroblasts on dendritic cells.
abstract: There is controversy about the immunomodulatory effect of fibroblasts on dendritic cells (DCs). To clarify this issue, in this study, we have evaluated different features of fibroblast-primed DCs including their ability to express co-inhibitory and co-stimulatory molecules, pro-inflammatory and anti-inflammatory cytokines and their ability to induce T-cell proliferation. We also examined migratory capacity of DCs to lymphatic tissues and present fibroblast-derived antigens after encountering fibroblasts. The results of our in vitro study showed that both co-inhibitory (programmed death ligand 1 and ligand 2 and B7H4) and co-stimulatory (CD86) molecules were up-regulated when DCs were co-cultured with fibroblasts. In an animal model, we showed that intra- peritoneal injection (IP) of both syngeneic and allogeneic fibroblasts significantly increased both total DC count and expression level of co-inhibitory and co-stimulatory molecules on DCs. Priming of DCs with syngeneic and allogeneic fibroblasts reduced the proliferation of CD4(+) and CD8(+) T cells. Even activation of fibroblast- primed DCs failed to restore their ability to induce T-cell proliferation. Likewise, priming of DCs with fibroblasts blocked the ability of ovalbumin-pulsed DCs to induce proliferation of ovalbumin-specific CD4(+) T cells. Compared with non-activated DCs, fibroblast-primed DCs had significantly higher expression levels of interleukin-10 and indoleamine 2, 3 dioxygenase. Fibroblast-primed DCs had a significantly reduced interleukin-12 expression level compared with that of activated DCs. After priming with fibroblasts, DCs were able to migrate to lymphatic tissues and present fibroblast-derived antigens (ovalbumin). In conclusion, after priming with fibroblasts, DCs gain tolerogenic features. This finding suggests the potential role of fibroblasts in the maintenance of immune tolerance.
authors.affiliation: Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khosravi-Maharlooei
authors.affiliation: Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: MohammadReza
authors.initials: M
authors.lastname: Pakyari
authors.affiliation: Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Reza B
authors.initials: RB
authors.lastname: Jalili
authors.affiliation: Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Sanam
authors.initials: S
authors.lastname: Salimi-Elizei
authors.affiliation: Department of Dermatology and Skin Science, Faculty of Medicine, Child and Family Research Institute, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jacqueline C Y
authors.initials: JC
authors.lastname: Lai
authors.affiliation: Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Malihesadat
authors.initials: M
authors.lastname: Poormasjedi-Meibod
authors.affiliation: Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ruhangiz T
authors.initials: RT
authors.lastname: Kilani
authors.affiliation: Department of Dermatology and Skin Science, Faculty of Medicine, Child and Family Research Institute, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jan
authors.initials: J
authors.lastname: Dutz
authors.affiliation: Department of Surgery, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines
keywords: Dermal fibroblasts; dendritic cells; tolerogenic effect