Role of innate signalling pathways in the immunogenicity of alphaviral replicon-based vaccines.
BACKGROUND
Alphaviral replicon-based vectors induce potent immune responses both when given as viral particles (VREP) or as DNA (DREP). It has been suggested that the strong immune stimulatory effect induced by these types of vectors is mediated by induction of danger signals and activation of innate signalling pathways due to the replicase activity. To investigate the innate signalling pathways involved, mice deficient in either toll-like receptors or downstream innate signalling molecules were immunized with DREP or VREP.


RESULTS
We show that the induction of a CD8+ T cell response did not require functional TLR3 or MyD88 signalling. However, IRF3, converging several innate signalling pathways and important for generation of pro-inflammatory cytokines and type I IFNs, was needed for obtaining a robust primary immune response. Interestingly, type I interferon (IFN), induced by most innate signalling pathways, had a suppressing effect on both the primary and memory T cell responses after DREP and VREP immunization.


CONCLUSIONS
We show that alphaviral replicon-based vectors activate multiple innate signalling pathways, which both activate and restrict the induced immune response. These results further show that there is a delicate balance in the strength of innate signalling and induction of adaptive immune responses that should be taken into consideration when innate signalling molecules, such as type I IFNs, are used as vaccine adjuvant.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels Väg 16, 17177 Stockholm, Sweden. Tanja.Naslund@ki.se
Tanja I
TI
Näslund
Linda
L
Kostic
Eva Kl
EK
Nordström
Margaret
M
Chen
Peter
P
Liljeström
D000524:Alphavirus / Q000235:genetics*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004337:Drug Carriers; D005260:Female; D005822:Genetic Vectors; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D014765:Viral Vaccines / Q000276:immunology*
D004337:Drug Carriers; D014765:Viral Vaccines
Nat Immunol. 2009 Jan;10(1):116-125
19029902
Nat Biotechnol. 2001 Jun;19(6):543-7
11385458
J Infect Dis. 2008 Nov 15;198(10):1482-90
18808335
Curr Opin Mol Ther. 2002 Feb;4(1):28-34
11883692
Expert Rev Vaccines. 2008 Mar;7(2):175-91
18324888
J Exp Med. 1999 Feb 1;189(3):521-30
9927514
Eur J Immunol. 2005 Mar;35(3):822-30
15724245
J Virol. 2007 Dec;81(24):13412-23
17913817
J Gen Virol. 2003 Feb;84(Pt 2):361-368
12560568
J Infect Dis. 2001 May 1;183(9):1395-8
11294672
Virology. 2005 Oct 25;341(2):190-202
16098555
Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):3009-13
7708765
Vaccine. 1999 Feb 5;17(5):497-507
10073729
Expert Rev Vaccines. 2008 Apr;7(3):373-81
18393607
Nat Med. 2003 Jan;9(1):33-9
12496961
J Immunol. 2002 Sep 15;169(6):3208-16
12218139
Adv Drug Deliv Rev. 2008 Apr 29;60(7):795-804
18262306
Nat Rev Immunol. 2008 May;8(5):327-36
18421305
J Virol. 2002 Jul;76(13):6652-9
12050378
J Gen Virol. 2005 Feb;86(Pt 2):349-354
15659754
J Virol. 2011 Jan;85(1):606-20
20962078
Curr Opin Infect Dis. 2005 Oct;18(5):387-94
16148524
J Immunol. 2006 Apr 15;176(8):4682-9
16585561
Ann N Y Acad Sci. 1995 Nov 27;772:261-4
8546403
J Virol. 1998 Feb;72(2):950-8
9444987
J Exp Med. 2007 Oct 29;204(11):2733-46
17954572
Immunity. 1998 May;8(5):591-9
9620680
Cancer Res. 2000 Jan 1;60(1):51-5
10646851
Nat Biotechnol. 2000 Sep;18(9):974-9
10973219
Vaccine. 2003 Mar 28;21(13-14):1363-70
12615431
Gene Ther. 2009 Mar;16(3):359-66
19052633
J Virol. 2011 Jan;85(1):315-23
20962088
Mol Ther. 2008 Feb;16(2):419-26
18087262
Mol Ther. 2005 Sep;12(3):451-9
15950543
Vaccine. 2006 Jun 12;24(24):5110-8
16725231
Nat Biotechnol. 1998 Jun;16(6):562-5
9624688
Nature. 2001 Oct 18;413(6857):732-8
11607032
Nat Med. 1999 Jul;5(7):823-7
10395329
J Virol. 2005 Mar;79(5):2964-72
15709016
J Immunol. 2006 Feb 15;176(4):2074-8
16455962
J Virol. 2007 Aug;81(16):8677-84
17553895
J Virol. 1991 Jan;65(1):147-54
1985194
Hum Gene Ther. 1995 Sep;6(9):1161-7
8527474
J Exp Med. 2008 Jan 21;205(1):63-77
18195071
Immunity. 1998 Jul;9(1):143-50
9697844
J Virol. 2010 Oct;84(20):10877-87
20686047
Biotechnology (N Y). 1991 Dec;9(12):1356-61
1370252
Immunity. 2000 Oct;13(4):539-48
11070172
Annu Rev Immunol. 2008;26:535-84
18303999
Nature. 2005 Feb 24;433(7028):887-92
15711573
Adv Drug Deliv Rev. 2008 Apr 29;60(7):847-57
18280611
Immunity. 2007 Sep;27(3):370-83
17892846
J Virol. 2010 Oct;84(19):10413-9
20631129
Adv Exp Med Biol. 2007;590:43-53
17191376
J Virol. 1999 Feb;73(2):1092-8
9882310
Biol Chem. 2008 May;389(5):541-5
18953720
Science. 1994 Jun 24;264(5167):1918-21
8009221
Nat Immunol. 2003 Oct;4(10):1009-15
14502286
Vaccine. 2004 Mar 29;22(11-12):1537-44
15063579
Nature. 2005 Apr 7;434(7034):772-7
15800576
Expert Rev Mol Med. 2008 Nov 11;10:e33
19000329
J Virol. 2009 Oct;83(20):10761-9
19656871
J Med Virol. 2005 Feb;75(2):249-57
15602727
Mol Biol Cell. 2005 Aug;16(8):3753-63
15930128
J Virol. 2006 Jul;80(14):7100-10
16809315
J Virol. 2005 Aug;79(16):10376-85
16051830
Vaccine. 2009 Sep 18;27(41):5700-8
19576940
Biochimie. 2007 Jun-Jul;89(6-7):744-53
17399883
Immunity. 2001 Apr;14(4):461-70
11336691