A New IRF-1-Driven Apoptotic Pathway Triggered by IL-4/IL-13 Kills Neonatal Th1 Cells and Weakens Protection against Viral Infection

J Immunol. 2019 Jun 1;202(11):3173-3186. doi: 10.4049/jimmunol.1800943. Epub 2019 Apr 17.

Abstract

Early life immune responses are deficient in Th1 lymphocytes that compromise neonatal vaccination. We found that IL-4 and IL-13 engage a developmentally expressed IL-4Rα/IL-13Rα1 heteroreceptor to endow IFN regulatory factor 1 (IRF-1) with apoptotic functions, which redirect murine neonatal Th1 reactivation to cell death. IL-4/IL-13-induced STAT6 phosphorylation serves to enhance IRF-1 transcription and promotes its egress from the nucleus. In the cytoplasm, IRF-1 can no longer serve as an anti-viral transcription factor but, instead, colocalizes with Bim and instigates the mitochondrial, or intrinsic, death pathway. The new pivotal function of IRF-1 in the death of neonatal Th1 cells stems from the ability of its gene to bind STAT6 for enhanced transcription and the proficiency of its protein to precipitate Bim-driven apoptosis. This cytokine-induced, IRF-1-mediated developmental death network weakens neonatal Th1 responses during early life vaccination and increases susceptibility to viral infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis
  • Bcl-2-Like Protein 11 / metabolism
  • Disease Resistance
  • Humans
  • Immunity
  • Infant, Newborn
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism*
  • Interleukin-13 / metabolism*
  • Interleukin-13 Receptor alpha1 Subunit / genetics
  • Interleukin-4 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction
  • Th1 Cells / immunology*
  • Viral Vaccines / immunology*
  • Virus Diseases / immunology*

Substances

  • Bcl-2-Like Protein 11
  • Interferon Regulatory Factor-1
  • Interleukin-13
  • Interleukin-13 Receptor alpha1 Subunit
  • STAT6 Transcription Factor
  • Viral Vaccines
  • Interleukin-4