Kennedy M K, Picha K S, Fanslow W C, Grabstein K H, Alderson M R, Clifford K N, Chin W A, Mohler K M
Immunex Corporation, Seattle, USA.
Eur J Immunol. 1996 Feb;26(2):370-8. doi: 10.1002/eji.1830260216.
We have previously shown that T cell receptor-activated mouse T helper (Th)1 clones induce the production of interleukin (IL)-12 by splenic antigen-presenting cells (APC). Here, we show that the expression of CD40L by activated T cells is critical for T cell-dependent IL-12 production by mouse macrophages. IL-12 was produced in cultures containing alloreactive Th1 clones stimulated with allogeneic peritoneal macrophages, or in cultures of splenocytes stimulated with anti-CD3. Anti-CD40L monoclonal antibodies (mAb) inhibited the production of IL-12, but not IL-2, in these cultures by approximately 90% and had dramatic inhibitory effects on antigen-dependent proliferation of Th1 clones. In addition, both activated T cells and a Th1 clone derived from CD40L knockout mice failed to induce IL-12 production from splenic APC or peritoneal macrophages. Finally, macrophages cultured in the absence of T cells produced IL-12 upon stimulation with soluble recombinant CD40L in combination with either supernatants from activated Th1 clones or with interferon-gamma and granulocyte/macrophage colony-stimulating factor. Thus, both CD40L-dependent and cytokine-mediated signals from activated T cells are required to induce the production of IL-12 by macrophages. A blockade at the level of IL-12 production may explain, at least in part, the dramatic ability of anti-CD40L mAb to inhibit disease in animal models that are dependent upon the generation of a cell-mediated immune response. Moreover, a defect in T cell-dependent induction of IL-12 may contribute to the immune status of humans that lack functional CD40L.
我们之前已经表明，T细胞受体激活的小鼠T辅助（Th）1克隆可诱导脾抗原呈递细胞（APC）产生白细胞介素（IL）-12。在此，我们表明活化T细胞上CD40L的表达对于小鼠巨噬细胞依赖T细胞产生IL-12至关重要。在含有同种异体反应性Th1克隆并用同种异体腹膜巨噬细胞刺激的培养物中，或在用抗CD3刺激的脾细胞培养物中可产生IL-12。抗CD40L单克隆抗体（mAb）在这些培养物中可将IL-12的产生抑制约90%，但对IL-2的产生无抑制作用，并且对Th1克隆的抗原依赖性增殖具有显著抑制作用。此外，活化T细胞和源自CD40L基因敲除小鼠的Th1克隆均不能诱导脾APC或腹膜巨噬细胞产生IL-12。最后，在无T细胞的情况下培养的巨噬细胞，在用可溶性重组CD40L与活化Th1克隆的上清液或与干扰素-γ和粒细胞/巨噬细胞集落刺激因子联合刺激时可产生IL-12。因此，活化T细胞的CD40L依赖性信号和细胞因子介导的信号均是诱导巨噬细胞产生IL-12所必需的。在IL-12产生水平的阻断至少可以部分解释抗CD40L mAb在依赖细胞介导免疫反应产生的动物模型中抑制疾病的显著能力。此外，T细胞依赖性诱导IL-12的缺陷可能导致缺乏功能性CD40L的人类的免疫状态。
