Bradley L M, Dalton D K, Croft M
Department of Biology, University of California, La Jolla 92093, USA.
J Immunol. 1996 Aug 15;157(4):1350-8.
IL-12 has been identified as a major cytokine influencing the differentiation of CD4 cells to a Th1 phenotype, whereas a role for IFN-gamma is controversial. We investigated the interrelationship between IL-12 and IFN-gamma in promoting Th1 responses using naive CD4 cells reactive with pigeon cytochrome c from TCR transgenics and memory CD4 cells derived by in vivo priming with KLH. Without exogenous rIL-12 or rIFN-gamma, primary and memory effectors induced by Ag or anti-CD3 and anti-CD28 secreted variable levels of IL-2 and IFN-gamma. The level of IFN-gamma secreted by effectors correlated with endogenous IFN-gamma produced in primary cultures, and anti-IFN-gamma largely inhibited the development of effectors producing IFN-gamma. With optimal TCR stimulation and costimulation, endogenous IFN-gamma, without IL-12, was sufficient to elicit Th1 cells via an autocrine mechanism, whereas with suboptimal stimulation, exogenous rIFN-gamma or rIL-12 was required for Th1 development. However, rIL-12 was more effective than rIFN-gamma, partially because rIL-12 greatly enhanced autocrine production of IFN-gamma, and optimal development of the Th1 phenotype was mediated by the synergistic actions of both cytokines. Thus, both IFN-gamma and IL-12 can independently regulate Th1 development, but because of IFN-gamma-mediated feedback, their relative contributions are determined by the conditions of T cell stimulation. The extent of differentiation to a Th1 phenotype may, therefore, depend on the availability of both APC-derived IL-12 and autocrine IFN-gamma consequent to the overall strength of T cell stimulation.
白细胞介素-12已被确定为影响CD4细胞分化为Th1表型的主要细胞因子，而干扰素-γ的作用则存在争议。我们使用来自TCR转基因小鼠的对鸽细胞色素c有反应的初始CD4细胞以及通过用钥孔血蓝蛋白进行体内致敏获得的记忆性CD4细胞，研究了白细胞介素-12和干扰素-γ在促进Th1反应中的相互关系。在没有外源性重组白细胞介素-12或重组干扰素-γ的情况下，由抗原或抗CD3和抗CD28诱导的初始效应细胞和记忆效应细胞分泌不同水平的白细胞介素-2和干扰素-γ。效应细胞分泌的干扰素-γ水平与原代培养物中产生的内源性干扰素-γ相关，抗干扰素-γ在很大程度上抑制了产生干扰素-γ的效应细胞的发育。在最佳的TCR刺激和共刺激下，没有白细胞介素-12时，内源性干扰素-γ足以通过自分泌机制引发Th1细胞，而在次优刺激下，Th1细胞的发育需要外源性重组干扰素-γ或重组白细胞介素-12。然而，重组白细胞介素-12比重组干扰素-γ更有效，部分原因是重组白细胞介素-12极大地增强了干扰素-γ的自分泌产生，并且Th1表型的最佳发育是由两种细胞因子的协同作用介导的。因此，干扰素-γ和白细胞介素-12都可以独立调节Th1细胞的发育，但由于干扰素-γ介导的反馈作用，它们的相对贡献取决于T细胞刺激的条件。因此，向Th1表型的分化程度可能取决于抗原呈递细胞衍生的白细胞介素-12的可用性以及T细胞刺激的总体强度所导致的自分泌干扰素-γ。
