title: CD40-deficient dendritic cells producing interleukin-10, but not interleukin-12, induce T-cell hyporesponsiveness in vitro and prevent acute allograft rejection.
abstract: The induction of an immune response or tolerance is mediated by corresponding subsets of dendritic cells (DC). However, the property of tolerogenic DC is not clear. Recently, we have characterized a population of CD11c+ splenic DC derived from long-term mixed leucocyte culture (LT-MLC), which are able to proliferate upon stimulation and have a strong primary mixed leucocyte reaction (MLR)-stimulating activity in conventional MLR. In this study, we show that, in contrast to the irradiated ones, non-irradiated LT-MLC-derived DC induce polyclonal antigen-specific T-cell hyporesponsiveness when cocultured with allogeneic splenocytes for 3-11 days. The degree of the hyporesponsiveness increased with the length of coculture. Although these DC expressed major histocompatibility complex class II and B7 costimulatory molecules, which are down-regulated during coculture, they expressed very low or undetectable CD40 before and after coculture, respectively. The CD40-deficient DC spontaneously produce interleukin-10 (IL-10), but not IL-12. The skewed balance between IL-10 and IL-12 is associated with their capability to induce T-cell hyporesponsiveness, because a neutralizing antibody to IL-10, exogenous recombinant IL-12 or lipopolysaccharide (LPS) significantly blocked the hyporesponsiveness. Accordingly, infusion of a small number of non-irradiated LT-MLC-derived DC (5x105) significantly prolonged the survival of a vascularized heterotopic murine heart transplant, whereas irradiated DC accelerated graft rejection. These data suggest that CD40-deficient DC producing IL-10, but not IL-12 can induce T-cell hyporesponsiveness in vitro and in vivo.
authors.affiliation: Transplantation and Immunobiology Group, The John P. Robarts Research Institute, London, Ont., Canada.
authors.forename: J X
authors.initials: JX
authors.lastname: Gao
authors.forename: J
authors.initials: J
authors.lastname: Madrenas
authors.forename: W
authors.initials: W
authors.lastname: Zeng
authors.forename: M J
authors.initials: MJ
authors.lastname: Cameron
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.forename: J J
authors.initials: JJ
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Zhong
authors.forename: D
authors.initials: D
authors.lastname: Grant
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D019013:CD40 Antigens; D008070:Lipopolysaccharides; D016753:Interleukin-10; D018664:Interleukin-12