PMID- 23658804
OWN - NLM
STAT- MEDLINE
DCOM- 20131204
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 5
DP  - 2013
TI  - Critical role of TLR7 signaling in the priming of cross-protective cytotoxic T 
      lymphocyte responses by a whole inactivated influenza virus vaccine.
PG  - e63163
LID - 10.1371/journal.pone.0063163 [doi]
LID - e63163
AB  - Current influenza vaccines fail to induce protection against antigenically 
      distinct virus strains. Accordingly, there is a need for the development of 
      cross-protective vaccines. Previously, we and others have shown that vaccination 
      with whole inactivated virus (WIV) induces cross-protective cellular immunity in 
      mice. To probe the mechanistic basis for this finding, we investigated the role 
      of TLR7, a receptor for single-stranded RNA, in induction of cross-protection. 
      Vaccination of TLR7-/- mice with influenza WIV failed to protect against a lethal 
      heterosubtypic challenge; in contrast, wild-type mice were fully protected. The 
      lack of protection in TLR7-/- mice was associated with high viral load and a 
      relative paucity of influenza-specific CD8+ cytotoxic T lymphocyte (CTL) 
      responses. Dendritic cells (DCs) from TLR7-/- mice were unable to cross-present 
      WIV-derived antigen to influenza-specific CTLs in vitro. Similarly, TLR7-/- DCs 
      failed to mature and become activated in response to WIV, as determined by the 
      assessment of surface marker expression and cytokine production. Plasmacytoid DCs 
      (pDCs) derived from wild-type mice responded directly to WIV while purified 
      conventional DCs (cDCs) did not respond to WIV in isolation, but were responsive 
      in mixed pDC/cDC cultures. Depletion of pDCs prior to and during WIV immunization 
      resulted in reduced numbers of influenza-specific CTLs and impaired protection 
      from heterosubtypic challenge. Thus, TLR7 plays a critical role in the induction 
      of cross-protective immunity upon vaccination with WIV. The initial target cells 
      for WIV appear to be pDCs which by direct or indirect mechanisms promote 
      activation of robust CTL responses against conserved influenza epitopes.
FAU - Budimir, Natalija
AU  - Budimir N
AD  - Molecular Virology Section, Department of Medical Microbiology, University of 
      Groningen, University Medical Center Groningen, Groningen, The Netherlands.
FAU - de Haan, Aalzen
AU  - de Haan A
FAU - Meijerhof, Tjarko
AU  - Meijerhof T
FAU - Waijer, Simke
AU  - Waijer S
FAU - Boon, Louis
AU  - Boon L
FAU - Gostick, Emma
AU  - Gostick E
FAU - Price, David A
AU  - Price DA
FAU - Wilschut, Jan
AU  - Wilschut J
FAU - Huckriede, Anke
AU  - Huckriede A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130502
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens, Viral)
RN  - 0 (Toll-Like Receptor 7)
RN  - 0 (Vaccines, Inactivated)
RN  - 0 (Viral Vaccines)
SB  - IM
MH  - Animals
MH  - Antigens, Viral/immunology
MH  - Cross Protection/*immunology
MH  - Cross-Priming/*immunology
MH  - Dendritic Cells/immunology
MH  - Dogs
MH  - Immunization
MH  - Influenza A Virus, H1N1 Subtype/immunology
MH  - Influenza A Virus, H5N1 Subtype/immunology
MH  - Influenza A virus/*immunology
MH  - Madin Darby Canine Kidney Cells
MH  - Mice
MH  - Signal Transduction/*immunology
MH  - Species Specificity
MH  - T-Lymphocytes, Cytotoxic/cytology/*immunology
MH  - Toll-Like Receptor 7/*metabolism
MH  - Vaccines, Inactivated/immunology
MH  - Viral Vaccines/*immunology
PMC - PMC3642048
COIS- Competing Interests: Louis Boon is Chief Scientific Officer at Bioceros. He 
      declares that he does not have competing interests due to this appointment nor 
      does this appointment alter his adherence to the PLOS ONE policies on sharing 
      data and materials.
EDAT- 2013/05/10 06:00
MHDA- 2013/12/16 06:00
PMCR- 2013/05/02
CRDT- 2013/05/10 06:00
PHST- 2013/02/09 00:00 [received]
PHST- 2013/03/28 00:00 [accepted]
PHST- 2013/05/10 06:00 [entrez]
PHST- 2013/05/10 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2013/05/02 00:00 [pmc-release]
AID - PONE-D-13-06237 [pii]
AID - 10.1371/journal.pone.0063163 [doi]
PST - epublish
SO  - PLoS One. 2013 May 2;8(5):e63163. doi: 10.1371/journal.pone.0063163. Print 2013.