title: Lipid motif of a bacterial antigen mediates immune responses via TLR2 signaling.
abstract: The cross-talk between the innate and the adaptive immune system is facilitated by the initial interaction of antigen with dendritic cells. As DCs express a large array of TLRs, evidence has accumulated that engagement of these molecules contributes to the activation of adaptive immunity. We have evaluated the immunostimulatory role of the highly-conserved outer membrane lipoprotein P6 from non-typeable Haemophilus influenzae (NTHI) to determine whether the presence of the lipid motif plays a critical role on its immunogenicity. We undertook a systematic analysis of the role that the lipid motif plays in the activation of DCs and the subsequent stimulation of antigen-specific T and B cells. To facilitate our studies, recombinant P6 protein that lacked the lipid motif was generated. Mice immunized with non-lipidated rP6 were unable to elicit high titers of anti-P6 Ig. Expression of the lipid motif on P6 was also required for proliferation and cytokine secretion by antigen-specific T cells. Upregulation of T cell costimulatory molecules was abrogated in DCs exposed to non-lipidated rP6 and in TLR2(-/-) DCs exposed to native P6, thereby resulting in diminished adaptive immune responses. Absence of either the lipid motif on the antigen or TLR2 expression resulted in diminished cytokine production from stimulated DCs. Collectively, our data suggest that the lipid motif of the lipoprotein antigen is essential for triggering TLR2 signaling and effective stimulation of APCs. Our studies establish the pivotal role of a bacterial lipid motif on activating both innate and adaptive immune responses to an otherwise poorly immunogenic protein antigen.
authors: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors: Amit A
authors: AA
authors: Lugade
authors: Anna
authors: A
authors: Bianchi-Smiraglia
authors: Vandana
authors: V
authors: Pradhan
authors: Galina
authors: G
authors: Elkin
authors: Timothy F
authors: TF
authors: Murphy
authors: Yasmin
authors: Y
authors: Thanavala
references: Expert Rev Vaccines. 2005 Dec;4(6):843-53
references: 16372880
references: Vaccine. 2008 Jan 10;26(2):201-14
references: 18063235
references: J Immunol. 2009 Aug 15;183(4):2785-92
references: 19635908
references: Am J Respir Crit Care Med. 2002 Apr 1;165(7):967-71
references: 11934723
references: Eur J Immunol. 2007 Nov;37(11):3040-53
references: 17918201
references: J Immunol. 2009 Jun 15;182(12):7459-72
references: 19494269
references: Vaccine. 2007 Jan 8;25(4):763-75
references: 16968658
references: Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15440-5
references: 15489266
references: Methods Mol Biol. 2008;494:247-61
references: 18726578
references: J Exp Med. 2007 Dec 24;204(13):3095-101
references: 18039950
references: Nature. 2005 Nov 17;438(7066):364-8
references: 16292312
references: Clin Exp Allergy. 2008 Nov;38(11):1819-29
references: 18644025
references: Science. 2006 Dec 22;314(5807):1936-8
references: 17185603
references: Infect Immun. 1990 Oct;58(10):3272-8
references: 2401565
references: Cell. 2006 Feb 24;124(4):849-63
references: 16497593
references: J Clin Immunol. 2008 Jul;28(4):361-9
references: 18379862
references: J Allergy Clin Immunol. 2009 Apr;123(4):875-82.e1
references: 19348925
references: J Immunol. 2009 Dec 15;183(12):7832-41
references: 19933854
references: Infect Immun. 2000 Aug;68(8):4505-17
references: 10899849
references: Vaccine. 2000 Dec 8;19 Suppl 1:S108-15
references: 11163473
references: J Immunol. 2009 Aug 15;183(4):2252-60
references: 19620295
references: PLoS One. 2008 May 21;3(5):e2257
references: 18493310
references: Clin Immunol. 2006 Oct;121(1):90-9
references: 16901757
references: Immunol Cell Biol. 2010 Nov-Dec;88(8):825-33
references: 20404835
references: Vaccine. 2009 May 18;27(23):3045-52
references: 19428918
references: Eur J Immunol. 2004 Nov;34(11):3102-14
references: 15368273
references: J Immunol. 2004 Apr 15;172(8):4733-43
references: 15067049
references: J Immunol. 2006 Jul 1;177(1):673-80
references: 16785566
references: Semin Immunol. 2009 Aug;21(4):185-93
references: 19502082
references: Infect Immun. 2007 Dec;75(12):5939-46
references: 17908810
references: Vaccine. 2008 Nov 11;26(48):6132-42
references: 18804504
references: Biochem Biophys Res Commun. 2004 Nov 19;324(3):1087-94
references: 15485666
references: Infect Immun. 2009 Sep;77(9):3939-47
references: 19596768
references: Viral Immunol. 2006 Summer;19(2):220-36
references: 16817765
references: J Immunol. 2009 Dec 1;183(11):6960-70
references: 19915052
references: J Immunol. 2005 Jun 15;174(12):7558-63
references: 15944255
references: Immunol Cell Biol. 2010 Jul;88(5):605-11
references: 20177411
references: Vaccine. 1999 Aug 20;18(1-2):29-37
references: 10501232
references: Infect Immun. 2001 Feb;69(2):773-8
references: 11159967
references: PLoS One. 2007 Sep 12;2(9):e863
references: 17848994
references: Vaccine. 2005 May 20;23(27):3590-6
references: 15855018
references: Vaccine. 2004 Jun 23;22(19):2494-9
references: 15193414
references: J Immunol. 2005 May 15;174(10):6308-13
references: 15879130
references: Infect Immun. 2005 Oct;73(10):6601-7
references: 16177336
references: FEMS Immunol Med Microbiol. 2006 Oct;48(1):44-55
references: 16965351
references: Cell Immunol. 2005 Jul-Aug;236(1-2):140-5
references: 16188245
references: BMC Immunol. 2009 Feb 04;10:9
references: 19193240