Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 22 December 2006:
Vol. 314. no. 5807, pp. 1936 - 1938
DOI: 10.1126/science.1135299
Prev | Table of Contents | Next

Reports

Adjuvant-Enhanced Antibody Responses in the Absence of Toll-Like Receptor Signaling

Amanda L. Gavin,1 Kasper Hoebe,1 Bao Duong,1,2 Takayuki Ota,1 Christopher Martin,1,2 Bruce Beutler,1 David Nemazee1*

Innate immune signals mediated by Toll-like receptors (TLRs) have been thought to contribute considerably to the antibody-enhancing effects of vaccine adjuvants. However, we report here that mice deficient in the critical signaling components for TLR mount robust antibody responses to T cell–dependent antigen given in four typical adjuvants: alum, Freund's complete adjuvant, Freund's incomplete adjuvant, and monophosphoryl-lipid A/trehalose dicorynomycolate adjuvant. We conclude that TLR signaling does not account for the action of classical adjuvants and does not fully explain the action of a strong adjuvant containing a TLR ligand. This may have important implications in the use and development of vaccine adjuvants.

1 Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037 USA.
2 The Scripps Research Institute, Kellogg School of Science and Technology, Doctoral Program in Chemical and Biological Sciences, La Jolla, CA 92037, USA.

* To whom correspondence should be addressed. E-mail: nemazee{at}scripps.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
TLR4 signaling augments B lymphocyte migration and overcomes the restriction that limits access to germinal center dark zones.
I.-Y. Hwang, C. Park, K. Harrison, and J. H. Kehrl (2009)
J. Exp. Med. 206, 2641-2657
   Abstract »    Full Text »    PDF »
Transverse myelitis and vaccines: a multi-analysis.
N. Agmon-Levin, S. Kivity, M. Szyper-Kravitz, and Y. Shoenfeld (2009)
Lupus 18, 1198-1204
   Abstract »    PDF »
Adjuvants and autoimmunity.
E. Israeli, N. Agmon-Levin, M. Blank, and Y. Shoenfeld (2009)
Lupus 18, 1217-1225
   Abstract »    PDF »
CD4 T cell cooperation is required for the in vivo activation of CD4 T cells.
N. C. Peters, D. R. Kroeger, S. Mickelwright, and P. A. Bretscher (2009)
Int. Immunol. 21, 1213-1224
   Abstract »    Full Text »    PDF »
Adjuvants Induce Distinct Immunological Phenotypes in a Bovine Tuberculosis Vaccine Model.
H. M. Vordermeier, G. S. Dean, I. Rosenkrands, E. M. Agger, P. Andersen, D. A. Kaveh, R. G. Hewinson, and P. J. Hogarth (2009)
Clin. Vaccine Immunol. 16, 1443-1448
   Abstract »    Full Text »    PDF »
Alum Induces Innate Immune Responses through Macrophage and Mast Cell Sensors, But These Sensors Are Not Required for Alum to Act As an Adjuvant for Specific Immunity.
A. S. McKee, M. W. Munks, M. K. L. MacLeod, C. J. Fleenor, N. Van Rooijen, J. W. Kappler, and P. Marrack (2009)
J. Immunol. 183, 4403-4414
   Abstract »    Full Text »    PDF »
Alveolar Macrophages and Lung Dendritic Cells Sense RNA and Drive Mucosal IgA Responses.
J. Bessa, A. Jegerlehner, H. J. Hinton, P. Pumpens, P. Saudan, P. Schneider, and M. F. Bachmann (2009)
J. Immunol. 183, 3788-3799
   Abstract »    Full Text »    PDF »
Vaccine-Induced Antibody Isotypes Are Skewed by Impaired CD4 T Cell and Invariant NKT Cell Effector Responses in MyD88-Deficient Mice.
O. I. Iweala, D. W. Smith, K. S. Matharu, I. Sada-Ovalle, D. D. Nguyen, R. H. DeKruyff, D. T. Umetsu, S. M. Behar, and C. R. Nagler (2009)
J. Immunol. 183, 2252-2260
   Abstract »    Full Text »    PDF »
Novel Generation Mycobacterial Adjuvant Based on Liposome-Encapsulated Monomycoloyl Glycerol from Mycobacterium bovis Bacillus Calmette-Guerin.
C. A. S. Andersen, I. Rosenkrands, A. W. Olsen, P. Nordly, D. Christensen, R. Lang, C. Kirschning, J. M. Gomes, V. Bhowruth, D. E. Minnikin, et al. (2009)
J. Immunol. 183, 2294-2302
   Abstract »    Full Text »    PDF »
Concomitant Inhalation of Cigarette Smoke and Aerosolized Protein Activates Airway Dendritic Cells and Induces Allergic Airway Inflammation in a TLR-Independent Way.
L. J. Robays, E. A. Lanckacker, K. B. Moerloose, T. Maes, K. R. Bracke, G. G. Brusselle, G. F. Joos, and K. Y. Vermaelen (2009)
J. Immunol. 183, 2758-2766
   Abstract »    Full Text »    PDF »
Innate and Adaptive Immunity Cooperate Flexibly to Maintain Host-Microbiota Mutualism.
E. Slack, S. Hapfelmeier, B. Stecher, Y. Velykoredko, M. Stoel, M. A. E. Lawson, M. B. Geuking, B. Beutler, T. F. Tedder, W.-D. Hardt, et al. (2009)
Science 325, 617-620
   Abstract »    Full Text »    PDF »
Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus.
D. H. Kono, M. K. Haraldsson, B. R. Lawson, K. M. Pollard, Y. T. Koh, X. Du, C. N. Arnold, R. Baccala, G. J. Silverman, B. A. Beutler, et al. (2009)
PNAS 106, 12061-12066
   Abstract »    Full Text »    PDF »
B Cell Intrinsic MyD88 Signals Drive IFN-{gamma} Production from T Cells and Control Switching to IgG2c.
T. A. Barr, S. Brown, P. Mastroeni, and D. Gray (2009)
J. Immunol. 183, 1005-1012
   Abstract »    Full Text »    PDF »
Interaction of the Hepatitis B Core Antigen and the Innate Immune System.
B. O. Lee, A. Tucker, L. Frelin, M. Sallberg, J. Jones, C. Peters, J. Hughes, D. Whitacre, B. Darsow, D. L. Peterson, et al. (2009)
J. Immunol. 182, 6670-6681
   Abstract »    Full Text »    PDF »
The Mucosal Adjuvant Effect of {alpha}-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection.
M. Lindqvist, J. Persson, K. Thorn, and A. M. Harandi (2009)
J. Immunol. 182, 6435-6443
   Abstract »    Full Text »    PDF »
BCR-mediated uptake of antigen linked to TLR9 ligand stimulates B-cell proliferation and antigen-specific plasma cell formation.
J. Eckl-Dorna and F. D. Batista (2009)
Blood 113, 3969-3977
   Abstract »    Full Text »    PDF »
Comparing Pooled Peptides with Intact Protein for Accessing Cross-presentation Pathways for Protective CD8+ and CD4+ T Cells.
H. Zhang, H. Hong, D. Li, S. Ma, Y. Di, A. Stoten, N. Haig, K. Di Gleria, Z. Yu, X.-N. Xu, et al. (2009)
J. Biol. Chem. 284, 9184-9191
   Abstract »    Full Text »    PDF »
Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif.
J. Lichtnekert, V. Vielhauer, D. Zecher, O. P. Kulkarni, S. Clauss, S. Segerer, V. Hornung, T. N. Mayadas, B. Beutler, S. Akira, et al. (2009)
Am J Physiol Renal Physiol 296, F867-F874
   Abstract »    Full Text »    PDF »
Immunostimulatory activity of haptenated proteins.
N. W. Palm and R. Medzhitov (2009)
PNAS 106, 4782-4787
   Abstract »    Full Text »    PDF »
Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge.
L. E. Cole, Y. Yang, K. L. Elkins, E. T. Fernandez, N. Qureshi, M. J. Shlomchik, L. A. Herzenberg, L. A. Herzenberg, and S. N. Vogel (2009)
PNAS 106, 4343-4348
   Abstract »    Full Text »    PDF »
NK Cell Enhancement of Antigen Presentation by B Lymphocytes.
P. Jennings and D. Yuan (2009)
J. Immunol. 182, 2879-2887
   Abstract »    Full Text »    PDF »
Innate Immunity Mediated by MyD88 Signal Is Not Essential for Induction of Lipopolysaccharide-Specific B Cell Responses but Is Indispensable for Protection against Salmonella enterica serovar Typhimurium infection.
H.-J. Ko, J.-Y. Yang, D.-H. Shim, H. Yang, S.-M. Park, R. Curtiss III, and M.-N. Kweon (2009)
J. Immunol. 182, 2305-2312
   Abstract »    Full Text »    PDF »
TLRs and innate immunity.
B. A. Beutler (2009)
Blood 113, 1399-1407
   Abstract »    Full Text »    PDF »
Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.
F. A. Sharp, D. Ruane, B. Claass, E. Creagh, J. Harris, P. Malyala, M. Singh, D. T. O'Hagan, V. Petrilli, J. Tschopp, et al. (2009)
PNAS 106, 870-875
   Abstract »    Full Text »    PDF »
Where Asthma and Hypersensitivity Pneumonitis Meet and Differ: Noneosinophilic Severe Asthma.
P. Bogaert, K. G. Tournoy, T. Naessens, and J. Grooten (2009)
Am. J. Pathol. 174, 3-13
   Abstract »    Full Text »    PDF »
CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization.
C. Sundling, K. Schon, A. Morner, M. N. E. Forsell, R. T. Wyatt, R. Thorstensson, G. B. K. Hedestam, and N. Y. Lycke (2008)
J. Gen. Virol. 89, 2954-2964
   Abstract »    Full Text »    PDF »
MyD88 Signaling Is Not Essential for Induction of Antigen-Specific B Cell Responses but Is Indispensable for Protection against Streptococcus pneumoniae Infection following Oral Vaccination with Attenuated Salmonella Expressing PspA Antigen.
S.-M. Park, H.-J. Ko, D.-H. Shim, J.-Y. Yang, Y.-H. Park, R. Curtiss III, and M.-N. Kweon (2008)
J. Immunol. 181, 6447-6455
   Abstract »    Full Text »    PDF »
Cutting Edge: Alum Adjuvant Stimulates Inflammatory Dendritic Cells through Activation of the NALP3 Inflammasome.
M. Kool, V. Petrilli, T. De Smedt, A. Rolaz, H. Hammad, M. van Nimwegen, I. M. Bergen, R. Castillo, B. N. Lambrecht, and J. Tschopp (2008)
J. Immunol. 181, 3755-3759
   Abstract »    Full Text »    PDF »
Toll-like receptors: lessons to learn from normal and malignant human B cells.
D. Chiron, I. Bekeredjian-Ding, C. Pellat-Deceunynck, R. Bataille, and G. Jego (2008)
Blood 112, 2205-2213
   Abstract »    Full Text »    PDF »
TLR Adaptor MyD88 Is Essential for Pathogen Control during Oral Toxoplasma gondii Infection but Not Adaptive Immunity Induced by a Vaccine Strain of the Parasite.
W. Sukhumavasi, C. E. Egan, A. L. Warren, G. A. Taylor, B. A. Fox, D. J. Bzik, and E. Y. Denkers (2008)
J. Immunol. 181, 3464-3473
   Abstract »    Full Text »    PDF »
Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin.
B. Liu and Z. Li (2008)
Blood 112, 1223-1230
   Abstract »    Full Text »    PDF »
Pyogenic Bacterial Infections in Humans with MyD88 Deficiency.
H. von Bernuth, C. Picard, Z. Jin, R. Pankla, H. Xiao, C.-L. Ku, M. Chrabieh, I. B. Mustapha, P. Ghandil, Y. Camcioglu, et al. (2008)
Science 321, 691-696
   Abstract »    Full Text »    PDF »
Differential Activation of Human and Mouse Toll-Like Receptor 4 by the Adjuvant Candidate LpxL1 of Neisseria meningitidis.
L. Steeghs, A. M. Keestra, A. van Mourik, H. Uronen-Hansson, P. van der Ley, R. Callard, N. Klein, and J. P. M. van Putten (2008)
Infect. Immun. 76, 3801-3807
   Abstract »    Full Text »    PDF »
The Agonists of TLR4 and 9 Are Sufficient to Activate Memory B Cells to Differentiate into Plasma Cells In Vitro but Not In Vivo.
K. Richard, S. K. Pierce, and W. Song (2008)
J. Immunol. 181, 1746-1752
   Abstract »    Full Text »    PDF »
Molecular and cellular signatures of human vaccine adjuvants.
F. Mosca, E. Tritto, A. Muzzi, E. Monaci, F. Bagnoli, C. Iavarone, D. O'Hagan, R. Rappuoli, and E. De Gregorio (2008)
PNAS 105, 10501-10506
   Abstract »    Full Text »    PDF »
Cutting Edge: Inflammasome Activation by Alum and Alum's Adjuvant Effect Are Mediated by NLRP3.
H. Li, S. B. Willingham, J. P.-Y. Ting, and F. Re (2008)
J. Immunol. 181, 17-21
   Abstract »    Full Text »    PDF »
Viral Double-Stranded RNA Triggers Ig Class Switching by Activating Upper Respiratory Mucosa B Cells through an Innate TLR3 Pathway Involving BAFF.
W. Xu, P. A. Santini, A. J. Matthews, A. Chiu, A. Plebani, B. He, K. Chen, and A. Cerutti (2008)
J. Immunol. 181, 276-287
   Abstract »    Full Text »    PDF »
Requirements for the natural killer cell-mediated induction of IgG1 and IgG2a expression in B lymphocytes.
N. Gao, P. Jennings, and D. Yuan (2008)
Int. Immunol. 20, 645-657
   Abstract »    Full Text »    PDF »
Gr1+IL-4-producing innate cells are induced in response to Th2 stimuli and suppress Th1-dependent antibody responses.
A. S. McKee, M. MacLeod, J. White, F. Crawford, J. W. Kappler, and P. Marrack (2008)
Int. Immunol. 20, 659-669
   Abstract »    Full Text »    PDF »
Role for MyD88 Signaling in Murine Gammaherpesvirus 68 Latency.
L. M. Gargano, J. M. Moser, and S. H. Speck (2008)
J. Virol. 82, 3853-3863
   Abstract »    Full Text »    PDF »
The Adjuvants Aluminum Hydroxide and MF59 Induce Monocyte and Granulocyte Chemoattractants and Enhance Monocyte Differentiation toward Dendritic Cells.
A. Seubert, E. Monaci, M. Pizza, D. T. O'Hagan, and A. Wack (2008)
J. Immunol. 180, 5402-5412
   Abstract »    Full Text »    PDF »
Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells.
M. Kool, T. Soullie, M. van Nimwegen, M. A.M. Willart, F. Muskens, S. Jung, H. C. Hoogsteden, H. Hammad, and B. N. Lambrecht (2008)
J. Exp. Med. 205, 869-882
   Abstract »    Full Text »    PDF »
Pivotal Advance: Eosinophils mediate early alum adjuvant-elicited B cell priming and IgM production.
H.-B. Wang and P. F. Weller (2008)
J. Leukoc. Biol. 83, 817-821
   Abstract »    Full Text »    PDF »
TLR Agonists Promote Marginal Zone B Cell Activation and Facilitate T-Dependent IgM Responses.
A. V. Rubtsov, C. L. Swanson, S. Troy, P. Strauch, R. Pelanda, and R. M. Torres (2008)
J. Immunol. 180, 3882-3888
   Abstract »    Full Text »    PDF »
Colonic Patches Direct the Cross-Talk Between Systemic Compartments and Large Intestine Independently of Innate Immunity.
S.-Y. Chang, H.-R. Cha, S. Uematsu, S. Akira, O. Igarashi, H. Kiyono, and M.-N. Kweon (2008)
J. Immunol. 180, 1609-1618
   Abstract »    Full Text »    PDF »
Ets-1 Regulates Plasma Cell Differentiation by Interfering with the Activity of the Transcription Factor Blimp-1.
S. A. John, J. L. Clements, L. M. Russell, and L. A. Garrett-Sinha (2008)
J. Biol. Chem. 283, 951-962
   Abstract »    Full Text »    PDF »
Interleukin-15 Increases Vaccine Efficacy through a Mechanism Linked to Dendritic Cell Maturation and Enhanced Antibody Titers.
K. U. Saikh, T. L. Kissner, S. Nystrom, G. Ruthel, and R. G. Ulrich (2008)
Clin. Vaccine Immunol. 15, 131-137
   Abstract »    Full Text »    PDF »
Receptor for Advanced Glycation End Products Expression on T Cells Contributes to Antigen-Specific Cellular Expansion In Vivo.
B. Moser, D. D. Desai, M. P. Downie, Y. Chen, S. F. Yan, K. Herold, A. M. Schmidt, and R. Clynes (2007)
J. Immunol. 179, 8051-8058
   Abstract »    Full Text »    PDF »
Agonists of Toll-Like Receptors 3, 4, 7, and 9 Are Candidates for Use as Adjuvants in an Outer Membrane Vaccine against Neisseria meningitidis Serogroup B.
F. Fransen, C. J. Boog, J. P. van Putten, and P. van der Ley (2007)
Infect. Immun. 75, 5939-5946
   Abstract »    Full Text »    PDF »
A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses.
K. Takahashi, T. Shibata, S. Akashi-Takamura, T. Kiyokawa, Y. Wakabayashi, N. Tanimura, T. Kobayashi, F. Matsumoto, R. Fukui, T. Kouro, et al. (2007)
J. Exp. Med. 204, 2963-2976
   Abstract »    Full Text »    PDF »
The Lipopolysaccharide Adjuvant Effect on T Cells Relies on Nonoverlapping Contributions from the MyD88 Pathway and CD11c+ Cells.
J. P. McAleer, D. J. Zammit, L. Lefrancois, R. J. Rossi, and A. T. Vella (2007)
J. Immunol. 179, 6524-6535
   Abstract »    Full Text »    PDF »
Primary Development and Participation in a Foreign Antigen-Driven Immune Response of a Chromatin-Reactive B Cell Clonotype Are Not Influenced by TLR9 or Other MyD88-Dependent TLRs.
F. Coffey, X. Liu, and T. Manser (2007)
J. Immunol. 179, 6663-6672
   Abstract »    Full Text »    PDF »
Danger-free autoimmune disease in Aire-deficient mice.
D. H. D. Gray, I. Gavanescu, C. Benoist, and D. Mathis (2007)
PNAS 104, 18193-18198
   Abstract »    Full Text »    PDF »
Autoimmunity Stimulated by Adoptively Transferred Dendritic Cells Is Initiated by Both {alpha}beta and {gamma}{delta} T Cells but Does Not Require MyD88 Signaling.
D. A. Martin, K. Zhang, J. Kenkel, G. Hughes, E. Clark, A. Davidson, and K. B. Elkon (2007)
J. Immunol. 179, 5819-5828
   Abstract »    Full Text »    PDF »
Selective predisposition to bacterial infections in IRAK-4 deficient children: IRAK-4 dependent TLRs are otherwise redundant in protective immunity.
C.-L. Ku, H. von Bernuth, C. Picard, S.-Y. Zhang, H.-H. Chang, K. Yang, M. Chrabieh, A. C. Issekutz, C. K. Cunningham, J. Gallin, et al. (2007)
J. Exp. Med. 204, 2407-2422
   Abstract »    Full Text »    PDF »
Sustained antigen presentation can promote an immunogenic T cell response, like dendritic cell activation.
R. Obst, H.-M. van Santen, R. Melamed, A. O. Kamphorst, C. Benoist, and D. Mathis (2007)
PNAS 104, 15460-15465
   Abstract »    Full Text »    PDF »
Neisseria meningitidis PorB, a TLR2 Ligand, Induces an Antigen-Specific Eosinophil Recall Response: Potential Adjuvant for Helminth Vaccines?.
J. M. Burke, L. M. Ganley-Leal, A. Khatri, and L. M. Wetzler (2007)
J. Immunol. 179, 3222-3230
   Abstract »    Full Text »    PDF »
BAFF and MyD88 signals promote a lupuslike disease independent of T cells.
J. R. Groom, C. A. Fletcher, S. N. Walters, S. T. Grey, S. V. Watt, M. J. Sweet, M. J. Smyth, C. R. Mackay, and F. Mackay (2007)
J. Exp. Med. 204, 1959-1971
   Abstract »    Full Text »    PDF »
The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-Biased Agonist of TLR4.
V. Mata-Haro, C. Cekic, M. Martin, P. M. Chilton, C. R. Casella, and T. C. Mitchell (2007)
Science 316, 1628-1632
   Abstract »    Full Text »    PDF »
TLR Agonists Selectively Promote Terminal Plasma Cell Differentiation of B Cell Subsets Specialized in Thymus-Independent Responses.
L. Genestier, M. Taillardet, P. Mondiere, H. Gheit, C. Bella, and T. Defrance (2007)
J. Immunol. 178, 7779-7786
   Abstract »    Full Text »    PDF »
Salmonella Induces a Switched Antibody Response without Germinal Centers That Impedes the Extracellular Spread of Infection.
A. F. Cunningham, F. Gaspal, K. Serre, E. Mohr, I. R. Henderson, A. Scott-Tucker, S. M. Kenny, M. Khan, K.-M. Toellner, P. J. L. Lane, et al. (2007)
J. Immunol. 178, 6200-6207
   Abstract »    Full Text »    PDF »
Tolls and Beyond -- Many Roads to Vaccine Immunity.
B. Pulendran (2007)
N. Engl. J. Med. 356, 1776-1778
   Full Text »    PDF »
Viral induction of AID is independent of the interferon and the Toll-like receptor signaling pathways but requires NF-{kappa}B.
P. Gourzi, T. Leonova, and F. N. Papavasiliou (2007)
J. Exp. Med. 204, 259-265
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)