Type I IFN and not TNF, is Essential for Cyclic Di-nucleotide-elicited CTL by a Cytosolic Cross-presentation Pathway
| Autor: | Ines Liebich, Verónica Durán, Darío Lirussi, Kai Schulze, Thomas Ebensen, Carlos A. Guzmán, Ulrich Kalinke, Stephanie Trittel |
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| Přispěvatelé: | Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany. |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CDN Cytosolic pathway Cellular immunity Type I IFN lcsh:Medicine Bone Marrow Cells CD8-Positive T-Lymphocytes Biology General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences Cross-Priming Immune system MHC class I Cyclic AMP Animals Cytotoxic T cell Cells Cultured lcsh:R5-920 Cross-presentation Tumor Necrosis Factor-alpha Antigen processing Vaccination lcsh:R General Medicine 3. Good health CTL 030104 developmental biology CDA Interferon Type I Immunology biology.protein lcsh:Medicine (General) Vaccine CD8 Research Paper Signal Transduction |
| Zdroj: | EBioMedicine, Vol 22, Iss C, Pp 100-111 (2017) EBioMedicine |
| ISSN: | 2352-3964 |
| Popis: | 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. Highlights • Cyclic di-AMP is a potent adjuvant with a proven capacity to promote cellular and humoral immunity. • It was postulated that type I IFN is irrelevant for CDA-generated immunity. • We show that CDA-mediated IFN-α/β signaling is essential for cytosolic cross-presentation, generating CTL by cross-priming. Antigen cross-presentation generates cross-priming of CD8 cytotoxic T cells (CTL), which kill intracellular pathogens and cancer cells. The generation of CTL is the main feature of cyclic di- nucleotide adjuvants (CDN). The production of type I IFN has been shown to be essential for the generation of CTL by other adjuvants, but not for cyclic di-AMP, a paramount CDN. Surprisingly, it was recently claimed that type I IFN is dispensable for the immunogenicity of CDN. We show here that type I IFN (and not TNF) is necessary for the cytosolic cross-presentation pathway activated by CDN, which results in CTL generation. This finding and the knowledge of the mechanism are of crucial importance for the safe development of CDN-adjuvanted vaccines. |
| Databáze: | OpenAIRE |
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