SCD2-mediated cooperative activation of IRF3-IRF9 regulatory circuit controls type I interferon transcriptome in CD4+ T cells

Front Immunol. 2022 Aug 18:13:904875. doi: 10.3389/fimmu.2022.904875. eCollection 2022.


Type I interferons (type I-IFN) are critical for the host defense to viral infection, and at the same time, the dysregulation of type I-IFN responses leads to autoinflammation or autoimmunity. Recently, we reported that the decrease in monounsaturated fatty acid caused by the genetic deletion of Scd2 is essential for the activation of type I-IFN signaling in CD4+ Th1 cells. Although interferon regulatory factor (IRF) is a family of homologous proteins that control the transcription of type I-IFN and interferon stimulated genes (ISGs), the member of the IRF family that is responsible for the type I-IFN responses induced by targeting of SCD2 remains unclear. Here, we report that the deletion of Scd2 triggered IRF3 activation for type I-IFN production, resulting in the nuclear translocation of IRF9 to induce ISG transcriptome in Th1 cells. These data led us to hypothesize that IRF9 plays an essential role in the transcriptional regulation of ISGs in Scd2-deleted (sgScd2) Th1 cells. By employing ChIP-seq analyses, we found a substantial percentage of the IRF9 target genes were shared by sgScd2 and IFNβ-treated Th1 cells. Importantly, our detailed analyses identify a unique feature of IRF9 binding in sgScd2 Th1 cells that were not observed in IFNβ-treated Th1 cells. In addition, our combined analyses of transcriptome and IRF9 ChIP-seq revealed that the autoimmunity related genes, which increase in patient with SLE, were selectively increased in sgScd2 Th1 cells. Thus, our findings provide novel mechanistic insights into the process of fatty acid metabolism that is essential for the type I-IFN response and the activation of the IRF family in CD4+ T cells.

Keywords: CD4+ T cells; ChIP-seq; IFR9; IRF3; RNA-seq; SCD2; fatty acid metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents
  • CD4-Positive T-Lymphocytes* / metabolism
  • Gene Expression Regulation
  • Humans
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Regulatory Factors* / genetics
  • Interferon Regulatory Factors* / metabolism
  • Interferon Type I* / metabolism
  • Interferon-Stimulated Gene Factor 3, gamma Subunit / metabolism
  • Stearoyl-CoA Desaturase* / genetics
  • Transcriptome


  • Antiviral Agents
  • IRF3 protein, human
  • IRF9 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Regulatory Factors
  • Interferon Type I
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • SCD5 protein, human
  • Stearoyl-CoA Desaturase