Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment

Arunakumar Gangaplara, Craig Martens, Eric Dahlstrom, Amina Metidji, Ameya S. Gokhale, Deborah D. Glass, Maria Lopez-Ocasio, Rachel Baur, Kishore Kanakabandi, Stephen F. Porcella, Ethan M. Shevach

Research output: Contribution to journalArticlepeer-review

Abstract

Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute, chronic infectious diseases and tumor microenvironment remains unclear. We recently demonstrated that IFN-α/β receptor (IFNAR) signaling promotes Treg function in autoimmunity. Here we dissected the functional role of IFNAR-signaling in Tregs using Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice in acute LCMV Armstrong, chronic Clone-13 viral infection, and in tumor models. In both viral infection and tumor models, IFNARfl/flxFoxp3YFP-Cremice Tregs expressed enhanced Treg associated activation antigens. LCMV-specific CD8+T cells and tumor infiltrating lymphocytes from IFNARfl/flxFoxp3YFP-Cremice produced less antiviral and antitumor IFN-γ and TNF-α. In chronic viral model, the numbers of antiviral effector and memory CD8+T cells were decreased in IFNARfl/flxFoxp3YFP-Cremice and the effector CD4+and CD8+T cells exhibited a phenotype compatible with enhanced exhaustion. IFNARfl/flxFoxp3YFP-Cremice cleared Armstrong infection normally, but had higher viral titers in sera, kidneys and lungs during chronic infection, and higher tumor burden than the WT controls. The enhanced activated phenotype was evident through transcriptome analysis of IFNARfl/flxFoxp3YFP-Cremice Tregs during infection demonstrated differential expression of a unique gene signature characterized by elevated levels of genes involved in suppression and decreased levels of genes mediating apoptosis. Thus, IFN signaling in Tregs is beneficial to host resulting in a more effective antiviral response and augmented antitumor immunity.

Original languageEnglish (US)
Article numbere1006985
JournalPLoS pathogens
Volume14
Issue number4
DOIs
StatePublished - Apr 2018
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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