T cell-derived IL-4 and dendritic cell-derived IL-12 regulate the lymphokine-producing phenotype of alloantigen-primed naive human CD4 T cells.
T cell-derived IL-4 and dendritic cell-derived IL-12 regulate the lymphokine-producing phenotype of alloantigen-primed naive human CD4 T cells.
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T 细胞衍生的 IL-4 和树突状细胞衍生的 IL-12 调节同种异体抗原引发的初始人类 CD4 T 细胞产生淋巴因子的表型。
DOI：
10.4049/jimmunol.158.2.629
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发表时间：
1997
影响因子：
4.4
通讯作者：
G. Delespesse
中科院分区：
文献类型：
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作者：
Y. Ohshima;G. Delespesse
先前对人类Th亚群发育的研究仅限于在没有生理性APC的情况下，用抗cd3单抗激活的幼稚T细胞。在这项研究中，我们分析了细胞因子和生理性APC对ag特异性系统中T细胞成熟的作用，在该系统中，幼稚的新生儿CD4 T细胞被异体树突状细胞（DC）引物。我们发现，启动细胞的细胞因子谱取决于1)T细胞和异体DC之间的比例，以及2)内源性IL-4和IL-12的产生。在原代MLR期间，IL-4的中和增加了启动时ifn - γ的产生，并将启动细胞的表型从Th0转移到Th1。这些作用依赖于IL-12，因为它们被抗IL-12抗体抑制。培养上清液中IL-12 p40的存在进一步证明了原代MLR中IL-12的产生。外源性IL-4抑制IL-12的产生，抗IL-4阻断单抗增加IL-12的产生，表明内源性IL-4下调DC的IL-12产生。最后，IL-12的产生是T细胞/DC相互作用的结果，涉及CD40/CD40配体和CD28/B7共刺激途径，如抗CD40配体mAb和CTLA-4Ig的抑制作用所揭示的。这些观察结果表明，在中性条件下，DC呈递Ag导致幼稚T细胞衍生的IL-4和DC衍生的IL-12协同产生，从而共同塑造Th细胞的细胞因子谱。
Previous studies on human Th subset development were restricted to the analysis of naive T cells activated with anti-CD3 mAb in the absence of physiologic APC. In this study, we have analyzed the role of cytokines and physiologic APC on T cell maturation in an Ag-specific system, in which naive neonatal CD4 T cells were primed with allogeneic dendritic cells (DC). We found that the cytokine profile of primed cells was dependent upon 1) the ratio between T cells and allogeneic DC and 2) the endogenous production of IL-4 and IL-12. Neutralization of IL-4 during primary MLR increased IFN-gamma production at priming and shifted the phenotype of primed cells from Th0 to Th1. These effects were IL-12 dependent, in that they were suppressed by anti-IL-12 Abs. The production of IL-12 in primary MLR was further evidenced by the presence of IL-12 p40 in the culture supernatant fluids. IL-12 production was suppressed by exogenous IL-4 and increased by anti-IL-4 blocking mAbs, indicating that endogenous IL-4 down-regulated IL-12 production by DC. Finally, IL-12 was produced as a result of T cell/DC interaction involving the CD40/CD40 ligand and CD28/B7 costimulation pathways, as revealed by the inhibitory effect of anti-CD40 ligand mAb and CTLA-4Ig. These observations suggest that in neutral conditions, Ag presentation by DC results in the coordinate production of naive T cell-derived IL-4 and DC-derived IL-12 that in concert shape the cytokine profile of Th cells.