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

  • Sci Signal. 2024 Apr 23;17(833):eadg5678. doi: 10.1126/scisignal.adg5678.
Emma L Bishop  1 ,  Nancy Gudgeon  1 ,  Taylor Fulton-Ward  1  2 ,  Victoria Stavrou  1 ,  Jennie Roberts  2 ,  Adam Boufersaoui  2 ,  Daniel A Tennant  2 ,  Martin Hewison  2 ,  Karim Raza  3  4 ,  Sarah Dimeloe  1  2
Affiliations
  • 1. Institute of Immunology and Immunotherapy, University of Birmingham, B15 2TT Birmingham, UK.
  • 2. Institute of Metabolism and Systems Research, University of Birmingham, B15 2TT Birmingham, UK.
  • 3. Research into Inflammatory Arthritis Centre Versus Arthritis, Institute of Inflammation and Ageing, University of Birmingham, B15 2TT Birmingham, UK.
  • 4. Sandwell and West Birmingham NHS Trust, B18 7QH Birmingham, UK.
PMID: 38652761 DOI: 10.1126/scisignal.adg5678
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.

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