Natural killer (NK) cell stimulatory factor or IL-12 has differential effects on the proliferation of TCR-alpha beta+, TCR-gamma delta+ T lymphocytes, and NK cells.
We have analyzed the effects of NK cell stimulatory factor/IL-12, on proliferation of PBL and their subsets. IL-12 synergizes with lectins and phorbol diesters to induce proliferation of CD4+ and CD8+ peripheral blood T lymphocytes. In the case of phorbol-diester-induced proliferation, the effect of IL-12 is in part mediated by induced IL-2 production, as suggested by the observation that IL-12 enhances IL-2 production in these cultures and that anti-IL-2 antibodies inhibit proliferation. IL-12 synergizes also with anti-CD3 antibodies and with allogeneic stimulation in MLC in inducing T cell proliferation. IL-12 alone is mitogenic for preactivated T and NK lymphoblasts. This mitogenic effect is observed with similar doses of IL-12 on NK lymphoblasts as well as on CD4+ and CD8+ TCR-alpha beta+ and on TCR-gamma delta+ lymphoblasts. On TCR-alpha beta+ T lymphocytes the effect of IL-12 is always additive to that of IL-2 over a wide dose range. The same effect is observed on highly activated, actively proliferating NK cells. However, on NK and TCR-gamma delta+ lymphoblasts reverting to a resting state after stimulation and on a TCR-gamma delta+ acute leukemia-derived T cell line, IL-12 inhibits significantly the proliferation induced by moderate to high doses (10 to 100 U/ml) of IL-2. This inhibitory effect is, at least in part, indirect, and depends on IL-12-induced production of TNF. Neutralizing anti-TNF antibodies, but not anti-IFN-gamma and anti-transforming growth factor antibodies, restore by more than 70% the inhibition of proliferation induced by IL-12 in these cultures. However, TNF alone cannot mimic the inhibitory effect of IL-12 on the IL-2-induced proliferation of NK and TCR-gamma delta+ lymphoblasts, suggesting the involvement of additional mechanisms. The relevance of these findings for the biology of lymphocyte subsets mediating MHC nonrestricted cytotoxicity is discussed.
Perussia
B
B
Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107.
Chan
S H
SH
D'Andrea
A
A
Tsuji
K
K
Santoli
D
D
Pospisil
M
M
Young
D
D
Wolf
S F
SF
Trinchieri
G
G
D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007376:Interleukin-2; D007378:Interleukins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma