Perussia B, Chan S H, D'Andrea A, Tsuji K, Santoli D, Pospisil M, Young D, Wolf S F, Trinchieri G
Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107.
J Immunol. 1992 Dec 1;149(11):3495-502.
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.
我们分析了NK细胞刺激因子/IL-12对外周血淋巴细胞（PBL）及其亚群增殖的影响。IL-12与凝集素和佛波酯协同作用，诱导CD4⁺和CD8⁺外周血T淋巴细胞增殖。在佛波酯诱导的增殖过程中，IL-12的作用部分是由诱导产生的IL-2介导的，这一观点得到了以下观察结果的支持：IL-12可增强这些培养物中IL-2的产生，且抗IL-2抗体可抑制增殖。IL-12还与抗CD3抗体以及混合淋巴细胞培养（MLC）中的同种异体刺激协同作用，诱导T细胞增殖。单独的IL-12对预激活的T和NK淋巴母细胞具有促有丝分裂作用。在NK淋巴母细胞以及CD4⁺和CD8⁺TCR-αβ⁺和TCR-γδ⁺淋巴母细胞上，观察到相似剂量的IL-12具有这种促有丝分裂作用。在TCR-αβ⁺T淋巴细胞上，在很宽的剂量范围内，IL-12的作用总是与IL-2的作用相加。在高度激活、活跃增殖的NK细胞上也观察到同样的效果。然而，在刺激后恢复到静止状态的NK和TCR-γδ⁺淋巴母细胞以及TCR-γδ⁺急性白血病来源的T细胞系上，IL-12可显著抑制中高剂量（10至100 U/ml）IL-2诱导的增殖。这种抑制作用至少部分是间接的，并且依赖于IL-12诱导的TNF产生。中和抗TNF抗体，但不是抗IFN-γ和抗转化生长因子抗体，可使这些培养物中IL-12诱导的增殖抑制恢复超过70%。然而，单独的TNF不能模拟IL-12对IL-2诱导的NK和TCR-γδ⁺淋巴母细胞增殖的抑制作用，这表明还涉及其他机制。讨论了这些发现对于介导MHC非限制性细胞毒性的淋巴细胞亚群生物学的相关性。
