Cutting Edge: Activation-Induced Iron Flux Controls CD4 T Cell Proliferation by Promoting Proper IL-2R Signaling and Mitochondrial Function

Yarosz, Emily L; Ye, Chenxian; Kumar, Ajay; Black, Chauna; Choi, Eun‐Kyung; Seo, Young-Ah; Chang, Ching-Pin

doi:10.4049/jimmunol.1901399

Cited by 37 publications

(31 citation statements)

References 27 publications

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“…Effects of iron deficiency inhibiting, and iron supplementation enhancing vaccine responses in humans have also been reported (6,7). Mechanistically, in vitro T-cell studies with iron starvation mediated via iron depleted media or the use of iron chelators demonstrate the importance of iron for cellular proliferation, activation and the production of effector molecules such as granzyme B (GZMB), granulocyte macrophage colony stimulating factor (GM-CSF) and interferon g (IFN-g) (3,5,(8)(9)(10). While a profound role for iron in T-cell activation and function has been established, the specific dynamics of iron utilisation, and the key biological processes affected within T-cells remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…In experimental studies, cellular iron deficiency could be achieved with either a high dose of DFO treatment for a short period of time (4–8 h, 100 µM to 1 mM) [ 34 , 35 , 36 ], or a low dose of DFO treatment for a relatively long period of time (24–48 h, 10–20 µM) [ 3 , 37 , 38 , 39 ]. We consider the former condition as acute iron deficiency and the latter condition as chronic iron deficiency, and the differential effects of either treatment remain largely unknown.…”

Section: Resultsmentioning

confidence: 99%

Iron Deficiency Reprograms Phosphorylation Signaling and Reduces O-GlcNAc Pathways in Neuronal Cells

et al. 2021

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Micronutrient sensing is critical for cellular growth and differentiation. Deficiencies in essential nutrients such as iron strongly affect neuronal cell development and may lead to defects in neuronal function that cannot be remedied by subsequent iron supplementation. To understand the adaptive intracellular responses to iron deficiency in neuronal cells, we developed and utilized a Stable Isotopic Labeling of Amino acids in Cell culture (SILAC)-based quantitative phosphoproteomics workflow. Our integrated approach was designed to comprehensively elucidate the changes in phosphorylation signaling under both acute and chronic iron-deficient cell models. In addition, we analyzed the differential cellular responses between iron deficiency and hypoxia (oxygen-deprived) in neuronal cells. Our analysis identified nearly 16,000 phosphorylation sites in HT-22 cells, a hippocampal-derived neuronal cell line, more than ten percent of which showed at least ≥2-fold changes in response to either hypoxia or acute/chronic iron deficiency. Bioinformatic analysis revealed that iron deficiency altered key metabolic and epigenetic pathways including the phosphorylation of proteins involved in iron sequestration, glutamate metabolism, and histone methylation. In particular, iron deficiency increased glutamine-fructose-6-phosphate transaminase (GFPT1) phosphorylation, which is a key enzyme in the glucosamine biosynthesis pathway and a target of 5′ AMP-activated protein kinase (AMPK), leading to reduced GFPT1 enzymatic activity and consequently lower global O-GlcNAc modification in neuronal cells. Taken together, our analysis of the phosphoproteome dynamics in response to iron and oxygen deprivation demonstrated an adaptive cellular response by mounting post-translational modifications that are critical for intracellular signaling and epigenetic programming in neuronal cells.

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“…Differentiation in the presence of heme resulted in increased oxidative phosphorylation. In T cells iron is important for activation induced proliferation and mitochondrial function (68). Thus, by upregulation of the components to import and generate heme, MBCs are primed to rapidly increase their metabolism towards modes that promote PC differentiation and support the demands of antibody secretion.…”

Section: Discussionmentioning

confidence: 99%

Conserved Epigenetic Programming and Enhanced Heme Metabolism Drive Memory B Cell Reactivation

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Kania

et al. 2021

The Journal of Immunology

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Memory B cells (MBCs) have enhanced capabilities to differentiate to plasma cells and generate a rapid burst of antibodies upon secondary stimulation. To determine if MBCs harbor an epigenetic landscape that contributes to increased differentiation potential, we derived the chromatin accessibility and transcriptomes of influenza-specific IgM and IgG MBCs compared to naïve cells. MBCs possessed an accessible chromatin architecture surrounding plasma cell specific genes, as well as altered expression of transcription factors and genes encoding cell cycle, chemotaxis, and signal transduction processes. Intriguingly, this MBC signature was conserved between humans and mice. MBCs of both species possessed a heightened heme signature compared to naïve cells. Differentiation in the presence of hemin enhanced oxidative phosphorylation metabolism and MBC differentiation into antibody secreting plasma cells. Thus, these data define conserved MBC transcriptional and epigenetic signatures that include a central role for heme and multiple other pathways in augmenting MBC reactivation potential.

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Cutting Edge: Activation-Induced Iron Flux Controls CD4 T Cell Proliferation by Promoting Proper IL-2R Signaling and Mitochondrial Function

Cited by 37 publications

References 27 publications

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

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

Iron Deficiency Reprograms Phosphorylation Signaling and Reduces O-GlcNAc Pathways in Neuronal Cells

Conserved Epigenetic Programming and Enhanced Heme Metabolism Drive Memory B Cell Reactivation

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