Type I IFN and not TNF, is Essential for Cyclic Di-nucleotide-elicited CTL by a Cytosolic Cross-presentation Pathway

EBioMedicine. 2017 Aug;22:100-111. doi: 10.1016/j.ebiom.2017.07.016. Epub 2017 Jul 19.

Abstract

Cyclic di-nucleotides (CDN) are potent stimulators of innate and adaptive immune responses. Cyclic di-AMP (CDA) is a promising adjuvant that generates humoral and cellular immunity. The strong STING-dependent stimulation of type I IFN represents a key feature of CDA. However, recent studies suggested that this is dispensable for adjuvanticity. Here we demonstrate that stimulation of IFN-γ-secreting CD8+ cytotoxic T lymphocytes (CTL) is significantly decreased after vaccination in the absence of type I IFN signaling. The biological significance of this CTL response was confirmed by the stimulation of MHC class I-restricted protection against influenza virus challenge. We show here that type I IFN (and not TNF-α) is essential for CDA-mediated cross-presentation by a cathepsin independent, TAP and proteosome dependent cytosolic antigen processing pathway, which promotes effective cross-priming and further CTL induction. Our data clearly demonstrate that type I IFN signaling is critical for CDN-mediated cross-presentation.

Keywords: CDA; CDN; CTL; Cross-presentation; Cytosolic pathway; Type I IFN; Vaccine.

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cross-Priming
  • Cyclic AMP / metabolism*
  • Interferon Type I / metabolism*
  • Mice
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism*
  • Vaccination

Substances

  • Interferon Type I
  • Tumor Necrosis Factor-alpha
  • Cyclic AMP