title: IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones.
abstract: We investigated the role of IL-12 in proliferation of various Th cell clones (class II-alloreactive (4-86 and 4-55) and keyhole limpet hemocyanin + self I-Ek-reactive (9-16)) following stimulation with Ag on APCs. These clones proliferated in response to stimulation with rIL-2, rIL-12, or Ag/APC. The proliferation induced by Ag/APC stimulation was not affected by anti-IL-2 Ab but was markedly inhibited by anti-IL-12 Abs. Consistent with this finding was the absence of detectable IL-2 activity in culture supernatants 12 to 48 h after Ag/APC stimulation, and the detection of significant levels of IL-12 in an Ab-capture bioassay. IL-12 was produced within 12 h after Ag/APC stimulation, reaching a peak after 18 to 24 h. The production of IL-12 in cultures of Th clones and APC contrasted with the production of IL-2 but not IL-12 upon allostimulation of primary T cells and the inhibition of their proliferation exclusively by anti-IL-2 Abs. Analysis of the expression of IL-12-binding sites on Th cells revealed low levels of IL-12 receptors in resting Th clones but high IL-12R levels 2 to 3 days after Ag/APC stimulation, declining gradually thereafter. The changes in IL-12R expression levels correlated closely with the IL-12 responsiveness of Th populations at various times after Ag/APC stimulation; Th populations obtained 3 and 10 days after Ag/APC stimulation exhibited very high and weak or marginal responsiveness to rIL-12, respectively, whereas the responses to rIL-2 were comparable in both Th populations. These results indicate that the Ag/APC-stimulated proliferation of terminally differentiated Th clones, in contrast to naive T cells, depends on the production of IL-12 by APC and on the simultaneous up-regulation of IL-12R on Th cells rather than on an IL-2 autocrine mechanism.
authors.affiliation: Biomedical Research Center, Osaka University Medical School, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Maruo
authors.forename: K
authors.initials: K
authors.lastname: Toyo-oka
authors.forename: M
authors.initials: M
authors.lastname: Oh-hora
authors.forename: X G
authors.initials: XG
authors.lastname: Tai
authors.forename: H
authors.initials: H
authors.lastname: Iwata
authors.forename: H
authors.initials: H
authors.lastname: Takenaka
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Ono
authors.forename: T
authors.initials: T
authors.lastname: Hamaoka
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: M
authors.initials: M
authors.lastname: Wysocka
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D002999:Clone Cells; D005260:Female; D007156:Immunologic Memory; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology / Q000494:pharmacology*; D007376:Interleukin-2 / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D018664:Interleukin-12