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Edited by Takeshi Saito, University of Southern California, Los Angeles, CA, and accepted by Editorial Board Member Carl F. Nathan January 25, 2017 (received for review August 8, 2016)
Significance
For many years, the development of adjuvants—compounds that boost the immunogenicity of vaccines—has been an empirical process. Adjuvants inducing a strong humoral immunity are available, but adjuvants directing the development of robust cellular immune responses are still needed. Recently, the C-type lectin receptor Mincle was found to elicit such responses on the recognition of microbial glycolipids, thereby providing a basis for the rational design of new adjuvants. Here we used a multidisciplinary approach, combining chemical synthesis, biology, and molecular modeling to decipher the molecular bases of ligand recognition by the receptor. This led us to synthesize new compounds inducing stronger immune responses than the currently available Mincle ligands that represent new powerful adjuvant molecules.
Abstract
The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cell-mediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6′-dimycolate (TDM), has opened avenues for the rational design of such molecules. Using a combination of chemical synthesis, biological evaluation, molecular dynamics simulations, and protein mutagenesis, we gained insight into the molecular bases of glycolipid recognition by Mincle. Unexpectedly, the fine structure of the fatty acids was found to play a key role in the binding of a glycolipid to the carbohydrate recognition domain of the lectin. Glucose and mannose esterified at O-6 by a synthetic α-ramified 32-carbon fatty acid showed agonist activity similar to that of TDM, despite their much simpler structure. Moreover, they were seen to stimulate proinflammatory cytokine production in primary human and murine cells in a Mincle-dependent fashion. Finally, they were found to induce strong Th1 and Th17 immune responses in vivo in immunization experiments in mice and conferred protection in a murine model of Mycobacterium tuberculosis infection. Here we describe the rational development of new molecules with powerful adjuvant properties.
Footnotes
↵1Present address: Research Department, GLYcoDiag, 45067 Orléans Cedex 2, France.
- ↵2To whom correspondence should be addressed: Email: jerome.nigou{at}ipbs.fr.
Author contributions: A.D., S.S.-G., D.D., S.B., I.A., F.J.C., T.L., D.S., E.P., A.V., J.P., M.G., G.T., and J.N. designed research; A.D., S.S.-G., S.B., I.A., and F.J.C. performed research; D.D., T.L., J.P., and M.G. contributed new reagents/analytic tools; A.D., S.S.-G., D.D., S.B., I.A., F.J.C., T.L., D.S., E.P., A.V., J.P., M.G., G.T., and J.N. analyzed data; and A.D., S.B., I.A., and J.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. T.S. is a Guest Editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1612421114/-/DCSupplemental.
- Alexiane Decouta,b,1,
- Sandro Silva-Gomesa,
- Daniel Drocourtb,
- Sophie Barbec,
- Isabelle Andréc,
- Francisco J. Cuetod,
- Thierry Liouxb,
- David Sanchod,
- Eric Pérouzelb,
- Alain Vercellonea,
- Jacques Prandia,
- Martine Gillerona,
- Gérard Tirabyb, and
- Jérôme Nigoua,2
- aInstitut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, F-31077 Toulouse, France;
- bResearch Department, InvivoGen, F-31400 Toulouse, France;
- cLaboratoire d'Ingénierie des Systèmes Biologiques et des Procédés, Université de Toulouse, CNRS, Institut National de la Recherche Agronomique (INRA), Institut National des Sciences Appliquées (INSA), F-31077 Toulouse, France;
- dCentro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid 28029, Spain
Edited by Takeshi Saito, University of Southern California, Los Angeles, CA, and accepted by Editorial Board Member Carl F. Nathan January 25, 2017 (received for review August 8, 2016)
Significance
For many years, the development of adjuvants—compounds that boost the immunogenicity of vaccines—has been an empirical process. Adjuvants inducing a strong humoral immunity are available, but adjuvants directing the development of robust cellular immune responses are still needed. Recently, the C-type lectin receptor Mincle was found to elicit such responses on the recognition of microbial glycolipids, thereby providing a basis for the rational design of new adjuvants. Here we used a multidisciplinary approach, combining chemical synthesis, biology, and molecular modeling to decipher the molecular bases of ligand recognition by the receptor. This led us to synthesize new compounds inducing stronger immune responses than the currently available Mincle ligands that represent new powerful adjuvant molecules.
Abstract
The advances in subunit vaccines development have intensified the search for potent adjuvants, particularly adjuvants inducing cell-mediated immune responses. Identification of the C-type lectin Mincle as one of the receptors underlying the remarkable immunogenicity of the mycobacterial cell wall, via recognition of trehalose-6,6′-dimycolate (TDM), has opened avenues for the rational design of such molecules. Using a combination of chemical synthesis, biological evaluation, molecular dynamics simulations, and protein mutagenesis, we gained insight into the molecular bases of glycolipid recognition by Mincle. Unexpectedly, the fine structure of the fatty acids was found to play a key role in the binding of a glycolipid to the carbohydrate recognition domain of the lectin. Glucose and mannose esterified at O-6 by a synthetic α-ramified 32-carbon fatty acid showed agonist activity similar to that of TDM, despite their much simpler structure. Moreover, they were seen to stimulate proinflammatory cytokine production in primary human and murine cells in a Mincle-dependent fashion. Finally, they were found to induce strong Th1 and Th17 immune responses in vivo in immunization experiments in mice and conferred protection in a murine model of Mycobacterium tuberculosis infection. Here we describe the rational development of new molecules with powerful adjuvant properties.
- mycobacteria
- glycolipid
- innate immunity
Footnotes
↵1Present address: Research Department, GLYcoDiag, 45067 Orléans Cedex 2, France.
- ↵2To whom correspondence should be addressed: Email: jerome.nigou{at}ipbs.fr.
Author contributions: A.D., S.S.-G., D.D., S.B., I.A., F.J.C., T.L., D.S., E.P., A.V., J.P., M.G., G.T., and J.N. designed research; A.D., S.S.-G., S.B., I.A., and F.J.C. performed research; D.D., T.L., J.P., and M.G. contributed new reagents/analytic tools; A.D., S.S.-G., D.D., S.B., I.A., F.J.C., T.L., D.S., E.P., A.V., J.P., M.G., G.T., and J.N. analyzed data; and A.D., S.B., I.A., and J.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. T.S. is a Guest Editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1612421114/-/DCSupplemental.
Adjuvants inducing a cellular immune response
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