Hilkens C M, Messer G, Tesselaar K, van Rietschoten A G, Kapsenberg M L, Wierenga E A
Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands.
J Immunol. 1996 Nov 15;157(10):4316-21.
IL-12 is a powerful skewer of CD4+ T cell responses toward the Th1 phenotype by inducing IFN-gamma production in naive Th cells. In the present study we addressed the question of whether IL-12 can reverse established Th2 responses into Th1/Th0 responses by inducing IFN-gamma production in memory Th2 cells. To this aim, allergen-specific CD4+ T cell clones (TCC) were generated from the peripheral blood of three atopic patients, and their cytokine profiles were analyzed. The majority of these TCC exhibited a strongly polarized Th2 cytokine profile, and the production of IFN-gamma could not be induced by exogenous IL-12. Only those TCC with low IFN-gamma levels in the absence of IL-12 responded to IL-12 by additional enhancement of IFN-gamma production. The IL-12 nonresponsiveness of the Th2 clones was further evident by the total lack of IL-12-induced phosphorylation of STAT4 (signal transducer and activator of transcription-4), a transcription factor that is typically involved in IL-12 signaling. Consequently, IL-12 also failed to induce the DNA-binding activity of STAT4-containing complexes in the nuclei of these Th2 clones. All TCC expressed equal levels of the low-affinity IL-12R beta1 subunit. Our results indicate that human allergen-specific Th cells with strongly polarized Th2 cytokine profiles do not respond to IL-12 and, therefore, cannot be induced to produce IFN-gamma. The apparent high frequency of IL-12-nonresponsive Th cells within the allergen-specific populations in atopic patients predicts a limited skewing potential of IL-12 in the case of established Th2 responses, but only affecting newly recruited naive Th cells.
白细胞介素-12（IL-12）通过诱导初始Th细胞产生γ干扰素（IFN-γ），有力地促使CD4+ T细胞反应向Th1表型偏移。在本研究中，我们探讨了IL-12能否通过诱导记忆性Th2细胞产生IFN-γ，将已确立的Th2反应逆转成Th1/Th0反应这一问题。为此，从三名特应性患者的外周血中分离出变应原特异性CD4+ T细胞克隆（TCC），并分析其细胞因子谱。这些TCC中的大多数呈现出强烈极化的Th2细胞因子谱，外源性IL-12无法诱导其产生IFN-γ。只有那些在无IL-12时IFN-γ水平较低的TCC，在IL-12作用下通过进一步增强IFN-γ产生而做出反应。Th2克隆对IL-12无反应性通过完全缺乏IL-12诱导的信号转导和转录激活因子4（STAT4）磷酸化进一步得到证明，STAT4是一种通常参与IL-12信号传导的转录因子。因此，IL-12也未能诱导这些Th2克隆细胞核中含STAT4复合物的DNA结合活性。所有TCC均表达同等水平的低亲和力IL-12Rβ1亚基。我们的结果表明，具有强烈极化Th2细胞因子谱的人变应原特异性Th细胞对IL-12无反应，因此不能被诱导产生IFN-γ。特应性患者变应原特异性群体中对IL-12无反应的Th细胞明显高频率存在，预示着在已确立Th2反应的情况下，IL-12的偏移潜力有限，但其仅影响新招募的初始Th细胞。
