Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression

• Verfasst von: Kamiński, Marcin [VerfasserIn]
• Verfasst von: Sauer, Sven [VerfasserIn]
• Verfasst von: Klemke, Claus-Detlev [VerfasserIn]
• Verfasst von: Süss, Dorothee [VerfasserIn]
• Verfasst von: Okun, Jürgen G. [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Gülow, Karsten [VerfasserIn]
• Titel: Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression
• Titelzusatz: mechanism of ciprofloxacin-mediated immunosuppression
• Verf.angabe: Marcin M. Kamiński, Sven W. Sauer, Claus-Detlev Klemke, Dorothee Süss, Jürgen G. Okun, Peter H. Krammer, Karsten Gülow
• E-Jahr: 2010
• Jahr: May 01 2010
• Umfang: 15 S.
• Fussnoten: Gesehen am 01.03.2023
• Titel Quelle: Enthalten in: The journal of immunology
• Ort Quelle: Bethesda, Md. : Soc., 1916
• Jahr Quelle: 2010
• Band/Heft Quelle: 184(2010), 9 vom: Mai, Seite 4827-4841
• ISSN Quelle: 1550-6606
• DOI: doi:10.4049/jimmunol.0901662
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1837791260

Abstract

This article shows that T cell activation-induced expression of the cytokines IL-2 and -4 is determined by an oxidative signal originating from mitochondrial respiratory complex I. We also report that ciprofloxacin, a fluoroquinolone antibiotic, exerts immunosuppressive effects on human T cells suppressing this novel mechanism. Sustained treatment of preactivated primary human T cells with ciprofloxacin results in a dose-dependent inhibition of TCR-induced generation of reactive oxygen species (ROS) and IL-2 and -4 expression. This is accompanied by the loss of mitochondrial DNA and a resulting decrease in activity of the complex I. Consequently, using a complex I inhibitor or small interfering RNA-mediated downregulation of the complex I chaperone NDUFAF1, we demonstrate that TCR-triggered ROS generation by complex I is indispensable for activation-induced IL-2 and -4 expression and secretion in resting and preactivated human T cells. This oxidative signal (H2O2) synergizes with Ca2+ influx for IL-2/IL-4 expression and facilitates induction of the transcription factors NF-κB and AP-1. Moreover, using T cells isolated from patients with atopic dermatitis, we show that inhibition of complex I-mediated ROS generation blocks disease-associated spontaneous hyperexpression and TCR-induced expression of IL-4. Prolonged ciprofloxacin treatment of T cells from patients with atopic dermatitis also blocks activation-induced expression and secretion of IL-4. Thus, our work shows that the activation phenotype of T cells is controlled by a mitochondrial complex I-originated oxidative signal.