Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation

Recent findings have shown that iron is a powerful regulator of immune responses, which is of broad importance because iron deficiency is highly prevalent worldwide. However, the underlying reasons of why iron is needed by lymphocytes remain unclear. Using a combination of mathematical modelling, bi...

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Autores principales: Megan R. Teh, Joe N. Frost, Andrew E. Armitage, Hal Drakesmith
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Lenguaje:EN
Publicado: Frontiers Media S.A. 2021
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Acceso en línea:https://doaj.org/article/73488ef543cd45f088afa4d81a16db5a
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spelling oai:doaj.org-article:73488ef543cd45f088afa4d81a16db5a2021-11-22T12:40:08ZAnalysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation1664-322410.3389/fimmu.2021.714613https://doaj.org/article/73488ef543cd45f088afa4d81a16db5a2021-08-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.714613/fullhttps://doaj.org/toc/1664-3224Recent findings have shown that iron is a powerful regulator of immune responses, which is of broad importance because iron deficiency is highly prevalent worldwide. However, the underlying reasons of why iron is needed by lymphocytes remain unclear. Using a combination of mathematical modelling, bioinformatic analysis and experimental work, we studied how iron influences T-cells. We identified iron-interacting proteins in CD4+ and CD8+ T-cell proteomes that were differentially expressed during activation, suggesting that pathways enriched with such proteins, including histone demethylation, may be impaired by iron deficiency. Consistent with this, iron-starved Th17 cells showed elevated expression of the repressive histone mark H3K27me3 and displayed reduced RORγt and IL-17a, highlighting a previously unappreciated role for iron in T-cell differentiation. Quantitatively, we estimated T-cell iron content and calculated that T-cell iron demand rapidly and substantially increases after activation. We modelled that these increased requirements will not be met during clinically defined iron deficiency, indicating that normalizing serum iron may benefit adaptive immunity. Conversely, modelling predicted that excess serum iron would not enhance CD8+ T-cell responses, which we confirmed by immunising inducible hepcidin knock-out mice that have very high serum iron concentrations. Therefore, iron deficiency impairs multiple aspects of T-cell responses, while iron overload likely has milder effects.Megan R. TehJoe N. FrostAndrew E. ArmitageHal DrakesmithHal DrakesmithFrontiers Media S.A.articleT-cellironimmunometabolismadaptive immunityiron deficiencydemethylationImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution DOAJ
collection DOAJ
language EN
topic T-cell
iron
immunometabolism
adaptive immunity
iron deficiency
demethylation
Immunologic diseases. Allergy
RC581-607
spellingShingle T-cell
iron
immunometabolism
adaptive immunity
iron deficiency
demethylation
Immunologic diseases. Allergy
RC581-607
Megan R. Teh
Joe N. Frost
Andrew E. Armitage
Hal Drakesmith
Hal Drakesmith
Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation
description Recent findings have shown that iron is a powerful regulator of immune responses, which is of broad importance because iron deficiency is highly prevalent worldwide. However, the underlying reasons of why iron is needed by lymphocytes remain unclear. Using a combination of mathematical modelling, bioinformatic analysis and experimental work, we studied how iron influences T-cells. We identified iron-interacting proteins in CD4+ and CD8+ T-cell proteomes that were differentially expressed during activation, suggesting that pathways enriched with such proteins, including histone demethylation, may be impaired by iron deficiency. Consistent with this, iron-starved Th17 cells showed elevated expression of the repressive histone mark H3K27me3 and displayed reduced RORγt and IL-17a, highlighting a previously unappreciated role for iron in T-cell differentiation. Quantitatively, we estimated T-cell iron content and calculated that T-cell iron demand rapidly and substantially increases after activation. We modelled that these increased requirements will not be met during clinically defined iron deficiency, indicating that normalizing serum iron may benefit adaptive immunity. Conversely, modelling predicted that excess serum iron would not enhance CD8+ T-cell responses, which we confirmed by immunising inducible hepcidin knock-out mice that have very high serum iron concentrations. Therefore, iron deficiency impairs multiple aspects of T-cell responses, while iron overload likely has milder effects.
format article
author Megan R. Teh
Joe N. Frost
Andrew E. Armitage
Hal Drakesmith
Hal Drakesmith
author_facet Megan R. Teh
Joe N. Frost
Andrew E. Armitage
Hal Drakesmith
Hal Drakesmith
author_sort Megan R. Teh
title Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation
title_short Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation
title_full Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation
title_fullStr Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation
title_full_unstemmed Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation
title_sort analysis of iron and iron-interacting protein dynamics during t-cell activation
publisher Frontiers Media S.A.
publishDate 2021
url https://doaj.org/article/73488ef543cd45f088afa4d81a16db5a
work_keys_str_mv AT meganrteh analysisofironandironinteractingproteindynamicsduringtcellactivation
AT joenfrost analysisofironandironinteractingproteindynamicsduringtcellactivation
AT andrewearmitage analysisofironandironinteractingproteindynamicsduringtcellactivation
AT haldrakesmith analysisofironandironinteractingproteindynamicsduringtcellactivation
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