title: Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells.
abstract: Interleukin-12 (IL-12), a 70-kDa heterodimeric cytokine composed of covalently linked p35 and p40 chains, is to date the most critical factor for skewing the immune response towards a T helper 1 (Th1) of cytokine profile [high interferon-gamma (IFN-gamma), low IL-4]. Established sources of IL-12 are stimulated macrophages, neutrophils and B cells. As dendritic cells (DC) process antigen in the periphery and then migrate to lymphoid organs to sensitize T cells and induce cell mediated immunity, we reasoned that DC should constitute a critical source of IL-12. The criteria used to detect IL-12 in DC were the demonstration of p40 and p35 mRNA (semiquantitative polymerase chain reaction, northern blotting, and in situ hybridization) as well as IL-12 protein (p70 enzyme-linked immunosorbent assay, p70 antigen capture followed by IFN-gamma bioassay, free p40 chain radioimmunoassay or immunoprecipitation). We found that conventional stimuli such as Staphylococcus aureus induced production of IL-12 by murine as well as human DC in amounts comparable to spleen cells, peritoneal macrophages or peripheral mononuclear cells. DC exhibited, however, features that had not been seen with other antigen-presenting cells: they produced bioactive IL-12 upon antigen-specific interaction with T cells without any other stimuli; in an allogeneic mixed leukocyte reaction model, neutralizing anti-IL-12 antibodies showed that DC-derived IL-12 was critical for optimal proliferation and IFN-gamma production by activated Th1 blasts; and finally, the priming of resting, naive allogeneic T cells by DC, followed by restimulation of primed T blasts by DC, skewed the response to Th1 without the need for any exogenous cytokines or stimuli such as microorganisms. This skewing to Th1 cytokine production, which depended on DC-derived IL-12, but did not require anti-IL-4, exogenous IL-12, or microbes, might be a major function of DC.
authors.affiliation: Department of Dermatology, University of Innsbruck, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Heufler
authors.forename: F
authors.initials: F
authors.lastname: Koch
authors.forename: U
authors.initials: U
authors.lastname: Stanzl
authors.forename: G
authors.initials: G
authors.lastname: Topar
authors.forename: M
authors.initials: M
authors.lastname: Wysocka
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
authors.forename: A
authors.initials: A
authors.lastname: Enk
authors.forename: R M
authors.initials: RM
authors.lastname: Steinman
authors.forename: N
authors.initials: N
authors.lastname: Romani
authors.forename: G
authors.initials: G
authors.lastname: Schuler
mesh_terms: D000818:Animals; D001483:Base Sequence; D002450:Cell Communication / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma