1. Academic Validation
  2. Mitochondrial reactive oxygen is critical for IL-12/IL-18-induced IFN-γ production by CD4+ T cells and is regulated by Fas/FasL signaling

Mitochondrial reactive oxygen is critical for IL-12/IL-18-induced IFN-γ production by CD4+ T cells and is regulated by Fas/FasL signaling

  • Cell Death Dis. 2022 Jun 6;13(6):531. doi: 10.1038/s41419-022-04907-5.
Gorjana Rackov  # 1 2 Parinaz Tavakoli Zaniani  # 3 Sara Colomo Del Pino 3 Rahman Shokri 3 4 Jorge Monserrat 5 6 Melchor Alvarez-Mon 5 6 7 Carlos Martinez-A 3 Dimitrios Balomenos 8
Affiliations

Affiliations

  • 1 Department of Immunology and Oncology, Centro Nacional de Biotecnología- Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain. rackov@bio.mx.
  • 2 BioMed X Institute (GmbH), Im Neuenheimer Feld 583, 69120, Heidelberg, Germany. rackov@bio.mx.
  • 3 Department of Immunology and Oncology, Centro Nacional de Biotecnología- Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain.
  • 4 Product and Research Complex, Pasteur Institute of Iran, Karaj, Iran.
  • 5 Department of Medicine and Medical Specialties, University Alcalá de Henares, Alcalá de Henares, Spain.
  • 6 Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain.
  • 7 Service of Internal Medicine and Immune System Diseases-Rheumatology, University Hospital Príncipe de Asturias, (CIBEREHD), Alcalá de Henares, Spain.
  • 8 Department of Immunology and Oncology, Centro Nacional de Biotecnología- Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain. dbalomenos@cnb.csic.es.
  • # Contributed equally.
Abstract

Mitochondrial activation and the production of mitochondrial Reactive Oxygen Species (mROS) are crucial for CD4+ T cell responses and have a role in naïve cell signaling after TCR activation. However, little is known about mROS role in TCR-independent signaling and in recall responses. Here, we found that mROS are required for IL-12 plus IL-18-driven production of IFN-γ, an essential cytokine for inflammatory and autoimmune disease development. Compared to TCR stimulation, which induced similar levels of mROS in naïve and memory-like cells, IL-12/IL-18 showed faster and augmented mROS production in memory-like cells. mROS inhibition significantly downregulated IFN-γ and CD44 expression, suggesting a direct mROS effect on memory-like T cell function. The mechanism that promotes IFN-γ production after IL-12/IL-18 challenge depended on the effect of mROS on optimal activation of downstream signaling pathways, leading to STAT4 and NF-κB activation. To relate our findings to IFN-γ-driven lupus-like disease, we used Fas-deficient memory-like CD4+ T cells from lpr mice. Importantly, we found significantly increased IFN-γ and mROS production in lpr compared with parental cells. Treatment of WT cells with FasL significantly reduced mROS production and the activation of signaling events leading to IFN-γ. Moreover, Fas deficiency was associated with increased mitochondrial levels of cytochrome C and Caspase-3 compared with WT memory-like cells. mROS inhibition significantly reduced the population of disease-associated lpr CD44hiCD62LloCD4+ T cells and their IFN-γ production. Overall, these findings uncovered a previously unidentified role of Fas/FasL interaction in regulating mROS production by memory-like T cells. This apoptosis-independent Fas activity might contribute to the accumulation of CD44hiCD62LloCD4+ T cells that produce increased IFN-γ levels in lpr mice. Overall, our findings pinpoint mROS as central regulators of TCR-independent signaling, and support mROS pharmacological targeting to control aberrant immune responses in autoimmune-like disease.

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