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T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein
The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-va...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552345/ https://www.ncbi.nlm.nih.gov/pubmed/28759640 http://dx.doi.org/10.1371/journal.ppat.1006469 |
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author | Fisher, Camilla R. Sutton, Henry J. Kaczmarski, Joe A. McNamara, Hayley A. Clifton, Ben Mitchell, Joshua Cai, Yeping Dups, Johanna N. D'Arcy, Nicholas J. Singh, Mandeep Chuah, Aaron Peat, Thomas S. Jackson, Colin J. Cockburn, Ian A. |
author_facet | Fisher, Camilla R. Sutton, Henry J. Kaczmarski, Joe A. McNamara, Hayley A. Clifton, Ben Mitchell, Joshua Cai, Yeping Dups, Johanna N. D'Arcy, Nicholas J. Singh, Mandeep Chuah, Aaron Peat, Thomas S. Jackson, Colin J. Cockburn, Ian A. |
author_sort | Fisher, Camilla R. |
collection | PubMed |
description | The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-validated modeling to analyze the binding of a murine neutralizing antibody to Plasmodium falciparum CSP. Strikingly, we found that the repeat region of CSP is bound by multiple antibodies. This repeating pattern allows multiple weak interactions of single F(AB) domains to accumulate and yield a complex with a dissociation constant in the low nM range. Because the CSP protein can potentially cross-link multiple B cell receptors (BCRs) we hypothesized that the B cell response might be T cell independent. However, while there was a modest response in mice deficient in T cell help, the bulk of the response was T cell dependent. By sequencing the BCRs of CSP-repeat specific B cells in inbred mice we found that these cells underwent somatic hypermutation and affinity maturation indicative of a T-dependent response. Last, we found that the BCR repertoire of responding B cells was limited suggesting that the structural simplicity of the repeat may limit the breadth of the immune response. |
format | Online Article Text |
id | pubmed-5552345 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-55523452017-08-25 T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein Fisher, Camilla R. Sutton, Henry J. Kaczmarski, Joe A. McNamara, Hayley A. Clifton, Ben Mitchell, Joshua Cai, Yeping Dups, Johanna N. D'Arcy, Nicholas J. Singh, Mandeep Chuah, Aaron Peat, Thomas S. Jackson, Colin J. Cockburn, Ian A. PLoS Pathog Research Article The repeat region of the Plasmodium falciparum circumsporozoite protein (CSP) is a major vaccine antigen because it can be targeted by parasite neutralizing antibodies; however, little is known about this interaction. We used isothermal titration calorimetry, X-ray crystallography and mutagenesis-validated modeling to analyze the binding of a murine neutralizing antibody to Plasmodium falciparum CSP. Strikingly, we found that the repeat region of CSP is bound by multiple antibodies. This repeating pattern allows multiple weak interactions of single F(AB) domains to accumulate and yield a complex with a dissociation constant in the low nM range. Because the CSP protein can potentially cross-link multiple B cell receptors (BCRs) we hypothesized that the B cell response might be T cell independent. However, while there was a modest response in mice deficient in T cell help, the bulk of the response was T cell dependent. By sequencing the BCRs of CSP-repeat specific B cells in inbred mice we found that these cells underwent somatic hypermutation and affinity maturation indicative of a T-dependent response. Last, we found that the BCR repertoire of responding B cells was limited suggesting that the structural simplicity of the repeat may limit the breadth of the immune response. Public Library of Science 2017-07-31 /pmc/articles/PMC5552345/ /pubmed/28759640 http://dx.doi.org/10.1371/journal.ppat.1006469 Text en © 2017 Fisher et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Fisher, Camilla R. Sutton, Henry J. Kaczmarski, Joe A. McNamara, Hayley A. Clifton, Ben Mitchell, Joshua Cai, Yeping Dups, Johanna N. D'Arcy, Nicholas J. Singh, Mandeep Chuah, Aaron Peat, Thomas S. Jackson, Colin J. Cockburn, Ian A. T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein |
title | T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein |
title_full | T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein |
title_fullStr | T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein |
title_full_unstemmed | T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein |
title_short | T-dependent B cell responses to Plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein |
title_sort | t-dependent b cell responses to plasmodium induce antibodies that form a high-avidity multivalent complex with the circumsporozoite protein |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552345/ https://www.ncbi.nlm.nih.gov/pubmed/28759640 http://dx.doi.org/10.1371/journal.ppat.1006469 |
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