Giuseppe
Emeritus
Programming the magnitude and persistence of antibody responses with innate immunity (Nature, abstract, edited)
[Source: Nature, full text: <cite cite="http://www.nature.com/nature/journal/v470/n7335/full/nature09737.html">Programming the magnitude and persistence of antibody responses with innate immunity : Nature : Nature Publishing Group</cite>. Abstract, edited.]
Programming the magnitude and persistence of antibody responses with innate immunity
* Sudhir Pai Kasturi,1, 2 * Ioanna Skountzou,1, 3 * Randy A. Albrecht,4 * Dimitrios Koutsonanos,3 * Tang Hua,1, 2 * Helder I. Nakaya,1, 2 * Rajesh Ravindran,1, 2 * Shelley Stewart,5 * Munir Alam,5 * Marcin Kwissa,1, 2 * Francois Villinger,1, 2, 6 * Niren Murthy,7 * John Steel,4 * Joshy Jacob,1, 2, 3 * Robert J. Hogan,8 * Adolfo Garc?a-Sastre,4, 9, 10 * Richard Compans1, 3 * & Bali Pulendran1, 2, 6
Journal name: Nature
Volume: 470, Pages: 543?547
Date published: (24 February 2011)
DOI: doi:10.1038/nature09737
Received 27 May 2010
Accepted 02 December 2010
Published online 23 February 2011
Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs)1, 2. For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed3, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines4, 5. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines6, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.
Subject terms: * Immunology
Affiliations
1. Emory Vaccine Center, Emory University, Atlanta, Georgia 30329, USA * Sudhir Pai Kasturi, * Ioanna Skountzou, * Tang Hua, * Helder I. Nakaya, * Rajesh Ravindran, * Marcin Kwissa, * Francois Villinger, * Joshy Jacob, * Richard Compans & * Bali Pulendran
2. Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA * Sudhir Pai Kasturi, * Tang Hua, * Helder I. Nakaya, * Rajesh Ravindran, * Marcin Kwissa, * Francois Villinger, * Joshy Jacob & * Bali Pulendran
3. Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30322, USA * Ioanna Skountzou, * Dimitrios Koutsonanos, * Joshy Jacob & * Richard Compans
4. Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA * Randy A. Albrecht, * John Steel & * Adolfo Garc?a-Sastre
5. Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina 103020, USA * Shelley Stewart & * Munir Alam
6. Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322, USA * Francois Villinger & * Bali Pulendran
7. The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA * Niren Murthy
8. Department of Anatomy and Radiology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, USA * Robert J. Hogan
9. Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York 10029, USA * Adolfo Garc?a-Sastre
10. Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 10029, USA * Adolfo Garc?a-Sastre
Contributions
S.P.K. and B.P. designed the study, planned the experiments and analysed the data. B.P. and S.P.K. wrote the manuscript. S.P.K., I.S. and B.P. designed and performed the H1N1 vaccine studies in mice and primates. D.K. assisted with the H1N1 vaccine studies in mice and primates. R.A.A., A.G.-S. and J.S. designed and performed the neutralization assays and challenge experiments with H5N1 vaccine studies in mice. T.H. and R.R. assisted with experiments. H.I.N. performed the microarray analysis. S.S. and M.A. designed and carried out the SPR-based avidity experiments. M.K. assisted with design and execution of mice and non-human primate experiments. N.M. assisted with design of formulations. J.J. assisted with immunohistochemistry and design of experiments. R.J.H. expressed and purified the recombinant H5HA protein. R.C. helped plan and design the H1N1 vaccine study in mice and primates.
Competing financial interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to: * Bali Pulendran
All microarray data are deposited in the Gene Expression Omnibus under accession number GSE25677.
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------<cite cite="http://www.nature.com/nature/journal/v470/n7335/full/nature09737.html"></cite>
[Source: Nature, full text: <cite cite="http://www.nature.com/nature/journal/v470/n7335/full/nature09737.html">Programming the magnitude and persistence of antibody responses with innate immunity : Nature : Nature Publishing Group</cite>. Abstract, edited.]
Programming the magnitude and persistence of antibody responses with innate immunity
* Sudhir Pai Kasturi,1, 2 * Ioanna Skountzou,1, 3 * Randy A. Albrecht,4 * Dimitrios Koutsonanos,3 * Tang Hua,1, 2 * Helder I. Nakaya,1, 2 * Rajesh Ravindran,1, 2 * Shelley Stewart,5 * Munir Alam,5 * Marcin Kwissa,1, 2 * Francois Villinger,1, 2, 6 * Niren Murthy,7 * John Steel,4 * Joshy Jacob,1, 2, 3 * Robert J. Hogan,8 * Adolfo Garc?a-Sastre,4, 9, 10 * Richard Compans1, 3 * & Bali Pulendran1, 2, 6
Journal name: Nature
Volume: 470, Pages: 543?547
Date published: (24 February 2011)
DOI: doi:10.1038/nature09737
Received 27 May 2010
Accepted 02 December 2010
Published online 23 February 2011
Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence indicates that they activate dendritic cells via Toll-like receptors (TLRs)1, 2. For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed3, activates dendritic cells via multiple TLRs to stimulate proinflammatory cytokines4, 5. Triggering specific combinations of TLRs in dendritic cells can induce synergistic production of cytokines6, which results in enhanced T-cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that program such antibody responses remains a major challenge in vaccinology. Here we demonstrate that immunization of mice with synthetic nanoparticles containing antigens plus ligands that signal through TLR4 and TLR7 induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with nanoparticles containing antigens plus a single TLR ligand. Consistent with this there was enhanced persistence of germinal centres and of plasma-cell responses, which persisted in the lymph nodes for >1.5 years. Surprisingly, there was no enhancement of the early short-lived plasma-cell response relative to that observed with single TLR ligands. Molecular profiling of activated B cells, isolated 7 days after immunization, indicated that there was early programming towards B-cell memory. Antibody responses were dependent on direct triggering of both TLRs on B cells and dendritic cells, as well as on T-cell help. Immunization protected completely against lethal avian and swine influenza virus strains in mice, and induced robust immunity against pandemic H1N1 influenza in rhesus macaques.
Subject terms: * Immunology
Affiliations
1. Emory Vaccine Center, Emory University, Atlanta, Georgia 30329, USA * Sudhir Pai Kasturi, * Ioanna Skountzou, * Tang Hua, * Helder I. Nakaya, * Rajesh Ravindran, * Marcin Kwissa, * Francois Villinger, * Joshy Jacob, * Richard Compans & * Bali Pulendran
2. Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA * Sudhir Pai Kasturi, * Tang Hua, * Helder I. Nakaya, * Rajesh Ravindran, * Marcin Kwissa, * Francois Villinger, * Joshy Jacob & * Bali Pulendran
3. Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30322, USA * Ioanna Skountzou, * Dimitrios Koutsonanos, * Joshy Jacob & * Richard Compans
4. Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA * Randy A. Albrecht, * John Steel & * Adolfo Garc?a-Sastre
5. Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina 103020, USA * Shelley Stewart & * Munir Alam
6. Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322, USA * Francois Villinger & * Bali Pulendran
7. The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA * Niren Murthy
8. Department of Anatomy and Radiology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602, USA * Robert J. Hogan
9. Department of Medicine, Division of Infectious Diseases, Mount Sinai School of Medicine, New York, New York 10029, USA * Adolfo Garc?a-Sastre
10. Global Health and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, New York 10029, USA * Adolfo Garc?a-Sastre
Contributions
S.P.K. and B.P. designed the study, planned the experiments and analysed the data. B.P. and S.P.K. wrote the manuscript. S.P.K., I.S. and B.P. designed and performed the H1N1 vaccine studies in mice and primates. D.K. assisted with the H1N1 vaccine studies in mice and primates. R.A.A., A.G.-S. and J.S. designed and performed the neutralization assays and challenge experiments with H5N1 vaccine studies in mice. T.H. and R.R. assisted with experiments. H.I.N. performed the microarray analysis. S.S. and M.A. designed and carried out the SPR-based avidity experiments. M.K. assisted with design and execution of mice and non-human primate experiments. N.M. assisted with design of formulations. J.J. assisted with immunohistochemistry and design of experiments. R.J.H. expressed and purified the recombinant H5HA protein. R.C. helped plan and design the H1N1 vaccine study in mice and primates.
Competing financial interests
The authors declare no competing financial interests.
Corresponding author
Correspondence to: * Bali Pulendran
All microarray data are deposited in the Gene Expression Omnibus under accession number GSE25677.
-
------<cite cite="http://www.nature.com/nature/journal/v470/n7335/full/nature09737.html"></cite>