1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [4] CIC IGR Curie 1428, 26 rue d'Ulm, 75005 Paris, France.
Nat Commun. 2014 May 28;5:3987. doi: 10.1038/ncomms4987.
In an inflammatory microenvironment, multiple cytokines may act on the same target cell, creating the possibility for combinatorial interactions. How these may influence the system-level function of a given cytokine is unknown. Here we show that a single cytokine, interferon (IFN)-alpha, can generate multiple transcriptional signatures, including distinct functional modules of variable flexibility, when acting in four cytokine environments driving distinct T helper cell differentiation programs (Th0, Th1, Th2 and Th17). We provide experimental validation of a chemokine, cytokine and antiviral modules differentially induced by IFN-α in Th1, Th2 and Th17 environments. Functional impact is demonstrated for the antiviral response, with a lesser IFN-α-induced protection to HIV-1 and HIV-2 infection in a Th17 context. Our results reveal that a single cytokine can induce multiple transcriptional and functional programs in different microenvironments. This combinatorial flexibility creates a previously unrecognized diversity of responses, with potential impact on disease physiopathology and cytokine therapy.
在炎症微环境中，多种细胞因子可能作用于同一靶细胞，从而产生组合相互作用的可能性。这些细胞因子如何影响特定细胞因子的系统功能尚不清楚。在这里，我们展示了一种细胞因子干扰素 (IFN)-α 在作用于四种细胞因子环境（Th0、Th1、Th2 和 Th17）以驱动不同的 T 辅助细胞分化程序时，可以产生多个转录特征，包括可变灵活性的不同功能模块。我们提供了实验验证，证明了趋化因子、细胞因子和抗病毒模块在 Th1、Th2 和 Th17 环境中被 IFN-α 差异诱导。抗病毒反应的功能影响得到了证明，在 Th17 环境中，HIV-1 和 HIV-2 感染的 IFN-α 诱导保护作用较小。我们的结果表明，一种细胞因子可以在不同的微环境中诱导多种转录和功能程序。这种组合灵活性产生了以前未被认识到的多种反应，可能对疾病病理生理学和细胞因子治疗产生影响。
