A direct role for IFN-gamma in regulation of Th1 cell development.
A direct role for IFN-gamma in regulation of Th1 cell development.
复制标题
DOI：
10.4049/jimmunol.157.4.1350
复制
发表时间：
1996-08
影响因子：
4.4
通讯作者：
L. Bradley;D. Dalton;M. Croft
中科院分区：
文献类型：
--
作者：
L. Bradley;D. Dalton;M. Croft
IL-12已被鉴定为影响CD 4细胞分化为Th 1表型的主要细胞因子，而IFN-γ的作用是有争议的。我们研究了IL-12和IFN-γ之间的相互关系，在促进Th 1反应，使用幼稚的CD 4细胞与鸽子细胞色素c的TCR转基因和记忆CD 4细胞来自体内引发与KLH。在没有外源性rIL-12或rIFN-γ的情况下，由Ag或抗CD 3和抗CD 28诱导的初级和记忆效应子分泌可变水平的IL-2和IFN-γ。效应子分泌的IFN-γ水平与原代培养物中产生的内源性IFN-γ相关，抗IFN-γ在很大程度上抑制了产生IFN-γ的效应子的发育。最佳的TCR刺激和共刺激，内源性IFN-γ，没有IL-12，是足以引起Th 1细胞通过自分泌机制，而与次优刺激，外源性rIFN-γ或rIL-12是必需的Th 1发展。然而，rIL-12比rIFN-γ更有效，部分原因是rIL-12极大地增强了IFN-γ的自分泌产生，并且Th 1表型的最佳发育由两种细胞因子的协同作用介导。因此，IFN-γ和IL-12都可以独立地调节Th 1的发育，但由于IFN-γ介导的反馈，它们的相对贡献由T细胞刺激的条件决定。因此，分化为Th 1表型的程度可能取决于APC衍生的IL-12和自分泌IFN-γ两者的可用性，这两者是T细胞刺激的总体强度的结果。
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.