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Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo
Adaptive immunity is mediated by antigen receptors that can induce weak or strong immune responses depending on the nature of the antigen that is bound. In T lymphocytes, antigen recognition triggers signal transduction by clustering T cell receptor (TCR)/CD3 multiprotein complexes. In addition, it...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646799/ https://www.ncbi.nlm.nih.gov/pubmed/26601285 http://dx.doi.org/10.1126/sciadv.1500415 |
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author | Hoffmann, Michele M. Molina-Mendiola, Carlos Nelson, Alfreda D. Parks, Christopher A. Reyes, Edwin E. Hansen, Michael J. Rajagopalan, Govindarajan Pease, Larry R. Schrum, Adam G. Gil, Diana |
author_facet | Hoffmann, Michele M. Molina-Mendiola, Carlos Nelson, Alfreda D. Parks, Christopher A. Reyes, Edwin E. Hansen, Michael J. Rajagopalan, Govindarajan Pease, Larry R. Schrum, Adam G. Gil, Diana |
author_sort | Hoffmann, Michele M. |
collection | PubMed |
description | Adaptive immunity is mediated by antigen receptors that can induce weak or strong immune responses depending on the nature of the antigen that is bound. In T lymphocytes, antigen recognition triggers signal transduction by clustering T cell receptor (TCR)/CD3 multiprotein complexes. In addition, it hypothesized that biophysical changes induced in TCR/CD3 that accompany receptor engagement may contribute to signal intensity. Nonclustering monovalent TCR/CD3 engagement is functionally inert despite the fact that it may induce changes in conformational arrangement or in the flexibility of receptor subunits. We report that the intrinsically inert monovalent engagement of TCR/CD3 can specifically enhance physiologic T cell responses to weak antigens in vitro and in vivo without stimulating antigen-unengaged T cells and without interrupting T cell responses to strong antigens, an effect that we term as “co-potentiation.” We identified Mono-7D6-Fab, which biophysically altered TCR/CD3 when bound and functionally enhanced immune reactivity to several weak antigens in vitro, including a gp100-derived peptide associated with melanoma. In vivo, Mono-7D6-Fab induced T cell antigen–dependent therapeutic responses against melanoma lung metastases, an effect that synergized with other anti-melanoma immunotherapies to significantly improve outcome and survival. We conclude that Mono-7D6-Fab directly co-potentiated TCR/CD3 engagement by weak antigens and that such concept can be translated into an immunotherapeutic design. The co-potentiation principle may be applicable to other receptors that could be regulated by otherwise inert compounds whose latent potency is only invoked in concert with specific physiologic ligands. |
format | Online Article Text |
id | pubmed-4646799 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46467992015-11-23 Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo Hoffmann, Michele M. Molina-Mendiola, Carlos Nelson, Alfreda D. Parks, Christopher A. Reyes, Edwin E. Hansen, Michael J. Rajagopalan, Govindarajan Pease, Larry R. Schrum, Adam G. Gil, Diana Sci Adv Research Articles Adaptive immunity is mediated by antigen receptors that can induce weak or strong immune responses depending on the nature of the antigen that is bound. In T lymphocytes, antigen recognition triggers signal transduction by clustering T cell receptor (TCR)/CD3 multiprotein complexes. In addition, it hypothesized that biophysical changes induced in TCR/CD3 that accompany receptor engagement may contribute to signal intensity. Nonclustering monovalent TCR/CD3 engagement is functionally inert despite the fact that it may induce changes in conformational arrangement or in the flexibility of receptor subunits. We report that the intrinsically inert monovalent engagement of TCR/CD3 can specifically enhance physiologic T cell responses to weak antigens in vitro and in vivo without stimulating antigen-unengaged T cells and without interrupting T cell responses to strong antigens, an effect that we term as “co-potentiation.” We identified Mono-7D6-Fab, which biophysically altered TCR/CD3 when bound and functionally enhanced immune reactivity to several weak antigens in vitro, including a gp100-derived peptide associated with melanoma. In vivo, Mono-7D6-Fab induced T cell antigen–dependent therapeutic responses against melanoma lung metastases, an effect that synergized with other anti-melanoma immunotherapies to significantly improve outcome and survival. We conclude that Mono-7D6-Fab directly co-potentiated TCR/CD3 engagement by weak antigens and that such concept can be translated into an immunotherapeutic design. The co-potentiation principle may be applicable to other receptors that could be regulated by otherwise inert compounds whose latent potency is only invoked in concert with specific physiologic ligands. American Association for the Advancement of Science 2015-10-02 /pmc/articles/PMC4646799/ /pubmed/26601285 http://dx.doi.org/10.1126/sciadv.1500415 Text en Copyright © 2015, The Authors http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Hoffmann, Michele M. Molina-Mendiola, Carlos Nelson, Alfreda D. Parks, Christopher A. Reyes, Edwin E. Hansen, Michael J. Rajagopalan, Govindarajan Pease, Larry R. Schrum, Adam G. Gil, Diana Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo |
title | Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo |
title_full | Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo |
title_fullStr | Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo |
title_full_unstemmed | Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo |
title_short | Co-potentiation of antigen recognition: A mechanism to boost weak T cell responses and provide immunotherapy in vivo |
title_sort | co-potentiation of antigen recognition: a mechanism to boost weak t cell responses and provide immunotherapy in vivo |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646799/ https://www.ncbi.nlm.nih.gov/pubmed/26601285 http://dx.doi.org/10.1126/sciadv.1500415 |
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