GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage

Callender, Lauren A.; Schroth, Johannes; Carroll, Elizabeth C.; Garrod-Ketchley, Conor; Romano, Lisa E.L.; Hendy, Eleanor; Kelly, A. Paul; Lavender, Paul; Akbar, Arne N.; Chapple, J. Paul; Henson, Sian M.

doi:10.1038/s41467-021-23715-7

Cited by 16 publications

(7 citation statements)

References 51 publications

(55 reference statements)

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“…We focused our attention on these proteins in the jejunum to examine their relationship with the mechanism regulating CD4+ T-cell differentiation, as well as the effects of LTA on these proteins. GATA3 promotes the differentiation of CD4+ T cells into Th2 cells . T-bet promotes the differentiation of CD4+ T cells into Th1 cells and releases IFN-γ, thereby regulating the inflammatory response .…”

Section: Discussionmentioning

confidence: 99%

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L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

Gong

et al. 2022

J. Agric. Food Chem.

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Ovalbumin (OVA), a common food protein, can cause deadly allergies with intestine-specific immune reactions. L-Theanine (LTA) shows great potential for regulating intestinal immunity. To investigate the regulatory effect of LTA intervention on intestine-specific immunity, a 41 day experiment was performed on BALB/c OVA-sensitized mice. The results show that injecting female mice intraperitoneally with 50 μg of OVA and administering 30 mg of OVA 4 times can successfully establish an OVAsensitized mouse model. LTA intervention significantly increased weight gain and thymus index (p < 0.05), decreased allergy and diarrhea scores (p < 0.05), and improved jejunum structure. Meanwhile, the histological score and degranulation of mast cells decreased. LTA intervention increased Clostridiales, Lachnospiraceae, Lactobacillus, Prevotella, and Ruminococcus abundance while decreasing Helicobacter abundance. Flow cytometry and Western blotting results indicated that 200 and 400 mg/kg of LTA upregulated the expression of T-bet and Foxp3 proteins (p < 0.05), thus promoting the differentiation of jejunum CD4+ T cells to Th1 and Tregs and increasing the cytokines IFN-γ, IL-10, and TGF-β (p < 0.05). We found that 200 and 400 mg/kg of LTA downregulated the expression of RORγt and GATA3, thus inhibiting the differentiation of Th2 and Th17 cells and decreasing cytokines IL-4, IL-5, IL-13 TNF-α, IL-6, and IL-17A (p < 0.05). LTA inhibited the degranulation of mast cells and significantly decreased the serum levels of OVA-IgE, HIS, and mouse MCPT-1 (p < 0.05). Therefore, LTA intervention alleviated OVA allergy by improving intestine-specific immunity.

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Section: Discussionmentioning

confidence: 99%

“…GATA3 promotes the differentiation of CD4+ T cells into Th2 cells. 52 T-bet promotes the differentiation of CD4+ T cells into Th1 cells and releases IFN-γ, thereby regulating the inflammatory response. 53 RORγt is a key transcription factor that controls the differentiation of Th17 cells.…”

Section: ■ Discussionmentioning

confidence: 99%

L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

Gong

et al. 2022

J. Agric. Food Chem.

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“…S1, B to C). Of more importance to our study, genes that were decreased in expression in the presence of anti–TNF-α (and therefore whose expression is normally driven by TNF-α signaling) included several metabolic genes, including LDHA and SDHC , which are involved in glycolysis and the TCA cycle, respectively; GATA3 , which is essential for T cell differentiation and is also implicated in mitochondrial function ( 24 ); and MYC, which encodes the key transcription factor c-Myc that regulates the metabolic activity of T cells (Fig. 2B) ( 25 , 26 ).…”

Section: Resultsmentioning

confidence: 99%

TNF-α signals through ITK-Akt-mTOR to drive CD4 ⁺ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis

Bishop,

Gudgeon,

Fulton-Ward

et al. 2024

Sci. Signal.

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Upon activation, T cells undergo metabolic reprogramming to meet the bioenergetic demands of clonal expansion and effector function. Because dysregulated T cell cytokine production and metabolic phenotypes coexist in chronic inflammatory disease, including rheumatoid arthritis (RA), we investigated whether inflammatory cytokines released by differentiating T cells amplified their metabolic changes. We found that tumor necrosis factor–α (TNF-α) released by human naïve CD4 + T cells upon activation stimulated the expression of a metabolic transcriptome and increased glycolysis, amino acid uptake, mitochondrial oxidation of glutamine, and mitochondrial biogenesis. The effects of TNF-α were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-κB pathway. TNF-α stimulated the differentiation of naïve cells into proinflammatory T helper 1 (T H 1) and T H 17 cells, but not that of regulatory T cells. CD4 + T cells from patients with RA showed increased TNF-α production and consequent Akt phosphorylation upon activation. These cells also exhibited increased mitochondrial mass, particularly within proinflammatory T cell subsets implicated in disease. Together, these findings suggest that T cell–derived TNF-α drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.

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“…Interestingly, mitochondrial reactive oxygen species could induce the activation of primary human T cells by regulating IL-2 and IL-4 expression [ 60 ]. GATA3, a cell-specific marker of TH2 cells, could modulate mitochondrial biogenesis and increase the mitochondrial content [ 61 , 62 ]. The abovementioned studies show that mitochondrial regulation, cell metabolism, and oxidative stress may play certain roles in the differentiation and activation of TH2 cells, which may be related to the difference in TH2 cell infiltration between the high- and low-risk groups.…”

Section: Discussionmentioning

confidence: 99%

Mitochondria-Related Transcriptome Characterization Associated with the Immune Microenvironment, Therapeutic Response and Survival Prediction in Pancreatic Cancer

Dong

Liu

Zhang

et al. 2023

IJMS

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(1) Background: Pancreatic cancer (PC) is one of the most lethal tumors. Mitochondrial dysfunction has been reported to be involved in cancer development; however, its role in PC has remained unclear. (2) Methods: The differentially expressed NMGs were selected between PC and normal pancreatic tissue. The NMG-related prognostic signature was established by LASSO regression. A nomogram was developed based on the 12-gene signature combined with other significant pathological features. An extensive analysis of the 12 critical NMGs was performed in multiple dimensions. The expression of some key genes was verified in our external cohort. (3) Results: Mitochondria-related transcriptome features was obviously altered in PC compared with normal pancreas tissue. The 12-NMG signature showed good performance in predicting prognosis in various cohorts. The high- and low-risk groups exhibited notable diversity in gene mutation characteristics, biological characteristics, chemotherapy response, and the tumor immune microenvironment. Critical gene expression was demonstrated in our cohort at the mRNA and protein levels and in organelle localization. (4) Conclusions: Our study analyzed the mitochondrial molecular characterization of PC, proving the crucial role of NMGs in PC development. The established NMG signature helps classify patient subtypes in terms of prognosis prediction, treatment response, immunological features, and biological function, providing a potential therapeutic strategy targeting mitochondrial transcriptome characterization.

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GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage

Cited by 16 publications

References 51 publications

L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

TNF-α signals through ITK-Akt-mTOR to drive CD4 ⁺ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis

Mitochondria-Related Transcriptome Characterization Associated with the Immune Microenvironment, Therapeutic Response and Survival Prediction in Pancreatic Cancer

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GATA3 induces mitochondrial biogenesis in primary human CD4+ T cells during DNA damage

Cited by 16 publications

References 51 publications

L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

L-Theanine Modulates Intestine-Specific Immunity by Regulating the Differentiation of CD4+ T Cells in Ovalbumin-Sensitized Mice

TNF-α signals through ITK-Akt-mTOR to drive CD4 + T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis

Mitochondria-Related Transcriptome Characterization Associated with the Immune Microenvironment, Therapeutic Response and Survival Prediction in Pancreatic Cancer

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Product

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TNF-α signals through ITK-Akt-mTOR to drive CD4 ⁺ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis