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TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.
- Source :
- Science Signaling; 4/23/2024, Vol. 17 Issue 833, p1-15, 15p
- Publication Year :
- 2024
-
Abstract
- 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<superscript>+</superscript> 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<subscript>H</subscript>1) and T<subscript>H</subscript>17 cells, but not that of regulatory T cells. CD4<superscript>+</superscript> 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. Editor's summary: Upon antigenic stimulation, T cells proliferate and gain effector functions, which require their metabolic reprogramming. Bishop et al. found that differentiating naïve human CD4<superscript>+</superscript> T cells released the cytokine TNF-α, which amplified their metabolic changes by stimulating Akt and mTOR signaling. Compared with CD4<superscript>+</superscript> T cells from healthy donors, those from patients with rheumatoid arthritis produced more TNF-α, showed increased Akt activation, and had increased mitochondrial mass within inflammatory cell subsets. These results suggest that TNF-α–mediated metabolic reprogramming is dysregulated during chronic inflammation. —John F. Foley [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19450877
- Volume :
- 17
- Issue :
- 833
- Database :
- Complementary Index
- Journal :
- Science Signaling
- Publication Type :
- Academic Journal
- Accession number :
- 176782421
- Full Text :
- https://doi.org/10.1126/scisignal.adg5678