IL-12 produced by antigen-presenting cells induces IL-2-independent proliferation of T helper cell clones.
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.
Maruo
S
S
Biomedical Research Center, Osaka University Medical School, Japan.
Toyo-oka
K
K
Oh-hora
M
M
Tai
X G
XG
Iwata
H
H
Takenaka
H
H
Yamada
S
S
Ono
S
S
Hamaoka
T
T
Kobayashi
M
M
Wysocka
M
M
Trinchieri
G
G
Fujiwara
H
H
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
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D018664:Interleukin-12