IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms
IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms
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DOI：
10.1073/pnas.2536517100
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发表时间：
2003-12-09
影响因子：
11.1
通讯作者：
de Sauvage, FJ
中科院分区：
文献类型：
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作者：
Lucas, S;Ghilardi, N;de Sauvage, FJ
IL-27是由抗原提呈细胞产生的一种新的异源二聚体细胞因子，它通过T细胞细胞因子受体(TCCR)(/WSX-1)在初始的CD4(+)T细胞和自然杀伤细胞上表达。TCCR/WSX-1缺陷导致T辅助细胞1型(T(H)1)发育迟缓，其机制尚未解决。我们在此报道，IL-27刺激发育中的小鼠T辅助细胞可以有效地诱导主要的T(H)1特异性转录因子T-bet及其下游靶标IL-12Rβ2的表达，而不依赖于干扰素-γ。此外，IL-27通过下调信号转导和转录激活因子(STAT)4抑制T(H)1发育的关键T(H)2特异性转录因子GATA-3的基础表达。IL-27通过TCCR/WSX-1诱导STAT1、STAT3、STAT4和Stat5的磷酸化。STAT1是抑制GATA-3所必需的，但IL-27对T-bet的诱导也可以通过不依赖STAT1的途径介导。尽管有类似T(H)1的信号转导模式，但IL-27不足以驱动CD4(+)T细胞分化为产生IFNGamma的细胞。同样，IL-27诱导原代自然杀伤细胞表达T-bet，但这不会导致干扰素-γ的产生或细胞毒活性的增加。因此，尽管IL-27本身不能驱动IFN-γ的产生，但它在T(H)1承诺的早期步骤中起着重要的作用，它以旁分泌的方式参与控制IL-12的反应性。
IL-27, a novel heterodimeric cytokine produced by antigen-presenting cells, signals through the T cell cytokine receptor (TCCR)(/WSX-1) expressed on naive CD4(+) T cells and natural killer cells. TCCR/WSX-1 deficiency results in delayed T helper type 1 (T(H)1) development through an unresolved mechanism. We report here that IL-27 stimulation in developing murine T helper cells potently induces the expression of the major T(H)1-specific transcription factor T-bet and its downstream target IL-12R beta2, independently of IFN-gamma. In addition, IL-27 suppresses basal expression of GATA-3, the critical T(H)2-specific transcription factor that inhibits T(H)1 development by down-regulating signal transducer and activator of transcription (Stat) 4. IL-27 signaling through TCCR/WSX-1 induces phosphorylation of Stat1, Stat3, Stat4, and Stat5. Stat1 is required for suppression of GATA-3, but T-bet induction by IL-27 can also be mediated through a Stat1-independent pathway. Despite its T(H)1-like signaling profile, IL-27 is not sufficient to drive the differentiation of CD4(+) T cells into IFNgamma-producing cells. Similarly, IL-27 induces T-bet expression in primary natural killer cells, but this does not result in an increase of IFNgamma production or cytotoxic activity. Therefore, although IL-27 is unable to drive IFNgamma production on its own, it plays an important role in the early steps of T(H)1 commitment by contributing in a paracrine manner to the control of IL-12 responsiveness.