Mehrotra P T, Grant A J, Siegel J P
Laboratory of Cellular Immunology, Food and Drug Administration, Rockville, MD 20852, USA.
J Immunol. 1995 May 15;154(10):5093-102.
We have previously demonstrated that human rIL-12 alone can augment the development of cytotoxic activity in stimulated CD8+ T cells. The present study was undertaken to examine the interactions of rIL-7 and rIL-12 on human peripheral blood T cell activation and CTL differentiation. Purified T lymphocytes were pulsed overnight with immobilized alpha-CD3 and then cultured for 3 additional days with IL-7 and/or IL-12. The combination of IL-7 and IL-12 synergistically enhanced the proliferation of either fresh CD3+ T cells or an IL-2-dependent CD4+ T cell line, Kit-225-K6. This synergy was seen on both subsets of T cells; however, CD8+ T cells were usually more responsive to IL-7 and IL-12 at lower concentrations than were CD4+ T cells. Furthermore, these cytokines additively/synergistically augmented the cytotoxic activity of CD8+ T cells. Abs to IL-2 and IL-2R alpha blocked the synergistic effect on proliferation of CD4+ T cells, but had a minimal effect on the synergistic response of the proliferative and cytotoxic activity of CD8+ T cells. Examination of the effects of IL-7 and IL-12 on the expression of IL-12 receptor on T cells revealed an increase in the subunit of IL-12R by IL-7 as determined by flow cytometric analysis. We analyzed the effects on IFN-gamma production by CD8+ T cells and found that IL-7 alone did not induce detectable levels of IFN-gamma production but together with IL-12 it synergistically enhanced the production of IFN-gamma. We also found that IFN-gamma was probably not required for enhanced CTL activity of CD8+ T cells, because Ab to human IFN-gamma did not block additive/synergistic effects of either cytokine. The synergistic stimulatory activity of IL-7 and IL-12 may be of significance in vivo and may provide an alternative mechanism of stimulating T cells for use in immunotherapy.
我们先前已经证明，单独的人重组白细胞介素-12（rIL-12）能够增强受刺激的CD8+ T细胞中细胞毒性活性的发展。本研究旨在检测rIL-7和rIL-12在人外周血T细胞活化和细胞毒性T淋巴细胞（CTL）分化方面的相互作用。纯化的T淋巴细胞用固定化的α-CD3脉冲过夜，然后用IL-7和/或IL-12再培养3天。IL-7和IL-12的组合协同增强了新鲜CD3+ T细胞或IL-2依赖的CD4+ T细胞系Kit-225-K6的增殖。这种协同作用在T细胞的两个亚群中均可见；然而，CD8+ T细胞通常在比CD4+ T细胞更低的浓度下对IL-7和IL-12更敏感。此外，这些细胞因子累加/协同增强了CD8+ T细胞的细胞毒性活性。抗IL-2和IL-2Rα抗体阻断了对CD4+ T细胞增殖的协同作用，但对CD8+ T细胞增殖和细胞毒性活性的协同反应影响极小。检测IL-7和IL-12对T细胞上IL-12受体表达的影响发现，通过流式细胞术分析确定，IL-7使IL-12R的亚基增加。我们分析了对CD8+ T细胞产生γ-干扰素（IFN-γ）的影响，发现单独的IL-7不会诱导可检测水平的IFN-γ产生，但与IL-12一起时，它协同增强了IFN-γ的产生。我们还发现，CD8+ T细胞增强的CTL活性可能不需要IFN-γ，因为抗人IFN-γ抗体不会阻断任何一种细胞因子的累加/协同作用。IL-7和IL-12的协同刺激活性在体内可能具有重要意义，并且可能为免疫治疗中刺激T细胞提供一种替代机制。
