Interferon‐γ and interleukin‐4 regulate T cell interleukin‐12 responsiveness through the differential modulation of high‐affinity interleukin‐12 receptor expression
Interferon‐γ and interleukin‐4 regulate T cell interleukin‐12 responsiveness through the differential modulation of high‐affinity interleukin‐12 receptor expression
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干扰素-γ 和白细胞介素-4 通过高亲和力白细胞介素-12 受体表达的差异调节来调节 T 细胞白细胞介素-12 反应性
DOI：
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发表时间：
1997
影响因子：
5.4
通讯作者：
J. Ritz
中科院分区：
文献类型：
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作者：
J. Gollob;Hiroshi Kawasaki;J. Ritz
干扰素-γ（IFN-γ）和白细胞介素-4（IL-4）是相互拮抗的细胞因子，可刺激CD 4 + T细胞发育为Th 1或Th 2细胞。小鼠中Th 2分化的一个特征是IL-12诱导的Jak 2和Stat 4活化的丧失，这伴随着不能响应IL-12产生IFN-γ。在这份报告中，我们发现，在IL-4存在下，用植物血凝素（PHA）激活的新鲜分离的人T细胞对IL-12的反应大大减弱，而用PHA + IFN-γ激活的T细胞的IL-12反应增强。放射性标记的IL-12结合研究表明，IL-4对T细胞IL-12反应性的损害与高亲和力IL-12受体表达的下调有关。相比之下，IFN-γ对IL-12反应性的增强与高亲和力IL-12受体表达的上调有关。通过使用新合成的针对低亲和力IL-12受体β亚基（IL-12 R β）的中和抗体，我们发现IL-4和IFN-γ都不影响IL-12 R β的表达，我们确定IL-12 R β是高亲和力IL-12结合所需的至少两个低亲和力亚基之一。这些发现表明，IL-4和IFN-γ通过差异调节低亲和力IL-12受体亚基的表达对T细胞IL-12反应性产生相反的作用，所述低亲和力IL-12受体亚基与IL-12 R β不同，并且与IL-12 R β一起需要高亲和力IL-12结合和IL-12反应性。这为理解不同细胞因子在细胞因子受体表达水平上的相互作用提供了基础，并提供了对Th 1和Th 2发展机制之一的了解。
Interferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) are mutually antagonistic cytokines that stimulate CD4+ T cells to develop into either Th1 or Th2 cells. One feature of Th2 differentiation in mice is the loss of IL‐12‐induced Jak2 and Stat4 activation, which is accompanied by the inability to produce IFN‐γ in response to IL‐12. In this report, we show that freshly isolated human T cells activated with phytohemagglutinin (PHA) in the presence of IL‐4 exhibit a greatly diminished response to IL‐12, whereas the IL‐12 response of T cells activated with PHA plus IFN‐γ is enhanced. Radiolabeled IL‐12 binding studies demonstrate that the impairment of T cell IL‐12 responsiveness by IL‐4 is associated with the down‐regulation of high‐affinity IL‐12 receptor expression. In contrast, the enhancement of IL‐12 responsiveness by IFN‐γ is associated with the up‐regulation of high‐affinity IL‐12 receptor expression. Through the use of a newly synthesized neutralizing antibody to the low‐affinity IL‐12 receptor β subunit (IL‐12Rβ), we show that neither IL‐4 nor IFN‐γ affect the expression of IL‐12Rβ, which we determine to be one of at least two low‐affinity subunits required for high‐affinity IL‐12 binding. These findings suggest that IL‐4 and IFN‐γ exert opposite effects on T cell IL‐12 responsiveness by differentially modulating the expression of low‐affinity IL‐12 receptor subunits that are distinct from IL‐12Rβ and required, together with IL‐12Rβ, for high‐affinity IL‐12 binding and IL‐12 responsiveness. This provides a basis for understanding the interplay between different cytokines at the level of cytokine receptor expression, and offers insight into one of the mechanisms governing Th1 and Th2 development.
影响因子：
4.4
作者：
B. Perussia;S. Chan;Annalisa D'Andrea;K. Tsuji;D. Santoli;M. Pospíšil;D. Young;S. Wolf;Giorgio Trinchieri
通讯作者：
B. Perussia;S. Chan;Annalisa D'Andrea;K. Tsuji;D. Santoli;M. Pospíšil;D. Young;S. Wolf;Giorgio Trinchieri