Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.

<h4>Background</h4>DC are activated by pathogen-associated molecular patterns (PAMPs), and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine scien...

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Autores principales:	Silvia A Fuertes Marraco, Clare L Scott, Philippe Bouillet, Annette Ives, Slavica Masina, David Vremec, Elisa S Jansen, Lorraine A O'Reilly, Pascal Schneider, Nicolas Fasel, Ken Shortman, Andreas Strasser, Hans Acha-Orbea
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b56d3e79d01545d096a0a06502ed8744
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spelling	oai:doaj.org-article:b56d3e79d01545d096a0a06502ed87442021-11-18T06:52:41ZType I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.1932-620310.1371/journal.pone.0020189https://doaj.org/article/b56d3e79d01545d096a0a06502ed87442011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21674051/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>DC are activated by pathogen-associated molecular patterns (PAMPs), and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine science due to their adjuvant potential, it is unclear whether and how PAMPs may affect DC viability. We aimed to elucidate the possible apoptotic mechanisms that control activated DC lifespan in response to PAMPs, particularly in vivo.<h4>Methodology/principal findings</h4>We report that polyinosinic:polycytidylic acid (PolyIC, synthetic analogue of dsRNA) induces dramatic apoptosis of mouse splenic conventional DC (cDC) in vivo, predominantly affecting the CD8α subset, as shown by flow cytometry-based analysis of splenic DC subsets. Importantly, while Bim deficiency conferred only minor protection, cDC depletion was prevented in mice lacking Bim plus one of three other BH3-only proteins, either Puma, Noxa or Bid. Furthermore, we show that Type I Interferon (IFN) is necessary and sufficient for DC death both in vitro and in vivo, and that TLR3 and MAVS co-operate in IFNß production in vivo to induce DC death in response to PolyIC.<h4>Conclusions/significance</h4>These results demonstrate for the first time in vivo that apoptosis restricts DC lifespan following activation by PolyIC, particularly affecting the CD8α cDC subset. Such DC apoptosis is mediated by the overlapping action of pro-apoptotic BH3-only proteins, including but not solely involving Bim, and is driven by Type I IFN. While Type I IFNs are important anti-viral factors, CD8α cDC are major cross-presenting cells and critical inducers of CTL. We discuss such paradoxical finding on DC death with PolyIC/Type I IFN. These results could contribute to understand immunosuppression associated with chronic infection, and to the optimization of DC-based therapies and the clinical use of PAMPs and Type I IFNs.Silvia A Fuertes MarracoClare L ScottPhilippe BouilletAnnette IvesSlavica MasinaDavid VremecElisa S JansenLorraine A O'ReillyPascal SchneiderNicolas FaselKen ShortmanAndreas StrasserHans Acha-OrbeaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 6, p e20189 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Silvia A Fuertes Marraco Clare L Scott Philippe Bouillet Annette Ives Slavica Masina David Vremec Elisa S Jansen Lorraine A O'Reilly Pascal Schneider Nicolas Fasel Ken Shortman Andreas Strasser Hans Acha-Orbea Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
description	<h4>Background</h4>DC are activated by pathogen-associated molecular patterns (PAMPs), and this is pivotal for the induction of adaptive immune responses. Thereafter, the clearance of activated DC is crucial to prevent immune pathology. While PAMPs are of major interest for vaccine science due to their adjuvant potential, it is unclear whether and how PAMPs may affect DC viability. We aimed to elucidate the possible apoptotic mechanisms that control activated DC lifespan in response to PAMPs, particularly in vivo.<h4>Methodology/principal findings</h4>We report that polyinosinic:polycytidylic acid (PolyIC, synthetic analogue of dsRNA) induces dramatic apoptosis of mouse splenic conventional DC (cDC) in vivo, predominantly affecting the CD8α subset, as shown by flow cytometry-based analysis of splenic DC subsets. Importantly, while Bim deficiency conferred only minor protection, cDC depletion was prevented in mice lacking Bim plus one of three other BH3-only proteins, either Puma, Noxa or Bid. Furthermore, we show that Type I Interferon (IFN) is necessary and sufficient for DC death both in vitro and in vivo, and that TLR3 and MAVS co-operate in IFNß production in vivo to induce DC death in response to PolyIC.<h4>Conclusions/significance</h4>These results demonstrate for the first time in vivo that apoptosis restricts DC lifespan following activation by PolyIC, particularly affecting the CD8α cDC subset. Such DC apoptosis is mediated by the overlapping action of pro-apoptotic BH3-only proteins, including but not solely involving Bim, and is driven by Type I IFN. While Type I IFNs are important anti-viral factors, CD8α cDC are major cross-presenting cells and critical inducers of CTL. We discuss such paradoxical finding on DC death with PolyIC/Type I IFN. These results could contribute to understand immunosuppression associated with chronic infection, and to the optimization of DC-based therapies and the clinical use of PAMPs and Type I IFNs.
format	article
author	Silvia A Fuertes Marraco Clare L Scott Philippe Bouillet Annette Ives Slavica Masina David Vremec Elisa S Jansen Lorraine A O'Reilly Pascal Schneider Nicolas Fasel Ken Shortman Andreas Strasser Hans Acha-Orbea
author_facet	Silvia A Fuertes Marraco Clare L Scott Philippe Bouillet Annette Ives Slavica Masina David Vremec Elisa S Jansen Lorraine A O'Reilly Pascal Schneider Nicolas Fasel Ken Shortman Andreas Strasser Hans Acha-Orbea
author_sort	Silvia A Fuertes Marraco
title	Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
title_short	Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
title_full	Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
title_fullStr	Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
title_full_unstemmed	Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.
title_sort	type i interferon drives dendritic cell apoptosis via multiple bh3-only proteins following activation by polyic in vivo.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/b56d3e79d01545d096a0a06502ed8744
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Type I interferon drives dendritic cell apoptosis via multiple BH3-only proteins following activation by PolyIC in vivo.

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