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Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses

Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabo...

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Autores principales: Bargiela, David, Cunha, Pedro P., Veliça, Pedro, Foskolou, Iosifina P., Barbieri, Laura, Rundqvist, Helene, Johnson, Randall S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891565/
https://www.ncbi.nlm.nih.gov/pubmed/35251031
http://dx.doi.org/10.3389/fimmu.2022.837669
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author Bargiela, David
Cunha, Pedro P.
Veliça, Pedro
Foskolou, Iosifina P.
Barbieri, Laura
Rundqvist, Helene
Johnson, Randall S.
author_facet Bargiela, David
Cunha, Pedro P.
Veliça, Pedro
Foskolou, Iosifina P.
Barbieri, Laura
Rundqvist, Helene
Johnson, Randall S.
author_sort Bargiela, David
collection PubMed
description Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabolic programs has been shown to boost or suppress immune responses in vitro and in vivo. Using publicly available T cell transcriptomic and proteomic datasets we identified vitamin B6-dependent transaminases as key metabolic enzymes driving T cell activation and differentiation. Inhibition of vitamin B6 metabolism using the pyridoxal 5’-phosphate (PLP) inhibitor, aminoxyacetic acid (AOA), suppresses CD8+ T cell proliferation and effector differentiation in a dose-dependent manner. We show that pyridoxal phosphate phosphatase (PDXP), a negative regulator of intracellular vitamin B6 levels, is under the control of the hypoxia-inducible transcription factor (HIF1), a central driver of T cell metabolism. Furthermore, by adoptive transfer of CD8 T cells into a C57BL/6 mouse melanoma model, we demonstrate the requirement for vitamin B6-dependent enzyme activity in mediating effective anti-tumor responses. Our findings show that vitamin B6 metabolism is required for CD8+ T cell proliferation and effector differentiation in vitro and in vivo. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy.
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spelling pubmed-88915652022-03-04 Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses Bargiela, David Cunha, Pedro P. Veliça, Pedro Foskolou, Iosifina P. Barbieri, Laura Rundqvist, Helene Johnson, Randall S. Front Immunol Immunology Targeting T cell metabolism is an established method of immunomodulation. Following activation, T cells engage distinct metabolic programs leading to the uptake and processing of nutrients that determine cell proliferation and differentiation. Redirection of T cell fate by modulation of these metabolic programs has been shown to boost or suppress immune responses in vitro and in vivo. Using publicly available T cell transcriptomic and proteomic datasets we identified vitamin B6-dependent transaminases as key metabolic enzymes driving T cell activation and differentiation. Inhibition of vitamin B6 metabolism using the pyridoxal 5’-phosphate (PLP) inhibitor, aminoxyacetic acid (AOA), suppresses CD8+ T cell proliferation and effector differentiation in a dose-dependent manner. We show that pyridoxal phosphate phosphatase (PDXP), a negative regulator of intracellular vitamin B6 levels, is under the control of the hypoxia-inducible transcription factor (HIF1), a central driver of T cell metabolism. Furthermore, by adoptive transfer of CD8 T cells into a C57BL/6 mouse melanoma model, we demonstrate the requirement for vitamin B6-dependent enzyme activity in mediating effective anti-tumor responses. Our findings show that vitamin B6 metabolism is required for CD8+ T cell proliferation and effector differentiation in vitro and in vivo. Targeting vitamin B6 metabolism may therefore serve as an immunodulatory strategy to improve anti-tumor immunotherapy. Frontiers Media S.A. 2022-02-17 /pmc/articles/PMC8891565/ /pubmed/35251031 http://dx.doi.org/10.3389/fimmu.2022.837669 Text en Copyright © 2022 Bargiela, Cunha, Veliça, Foskolou, Barbieri, Rundqvist and Johnson https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Bargiela, David
Cunha, Pedro P.
Veliça, Pedro
Foskolou, Iosifina P.
Barbieri, Laura
Rundqvist, Helene
Johnson, Randall S.
Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses
title Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses
title_full Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses
title_fullStr Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses
title_full_unstemmed Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses
title_short Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses
title_sort vitamin b6 metabolism determines t cell anti-tumor responses
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891565/
https://www.ncbi.nlm.nih.gov/pubmed/35251031
http://dx.doi.org/10.3389/fimmu.2022.837669
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