TNF-α signals through ITK-Akt-mTOR to drive CD4+ T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis.
Sci Signal
; 17(833): eadg5678, 2024 Apr 23.
Article
em En
| MEDLINE
| ID: mdl-38652761
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+ 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 (TH1) and TH17 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
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Linfócitos T CD4-Positivos
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Transdução de Sinais
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Fator de Necrose Tumoral alfa
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Proteínas Proto-Oncogênicas c-akt
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Serina-Treonina Quinases TOR
Limite:
Humans
Idioma:
En
Revista:
Sci Signal
Assunto da revista:
CIENCIA
/
FISIOLOGIA
Ano de publicação:
2024
Tipo de documento:
Article