TNF-α signals through ITK-Akt-mTOR to drive CD4 T cell metabolic reprogramming, which is dysregulated in rheumatoid arthritis
Bishop, Emma L Gudgeon, Nancy Fulton-Ward, Taylor Stavrou, Victoria Roberts, Jennie Boufersaoui, Adam Tennant, Daniel A Hewison, Martin Raza, Karim Dimeloe, Sarah
Bishop, Emma L
Gudgeon, Nancy
Fulton-Ward, Taylor
Stavrou, Victoria
Roberts, Jennie
Boufersaoui, Adam
Tennant, Daniel A
Hewison, Martin
Raza, Karim
Dimeloe, Sarah
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Affiliation
Institute of Immunology and Immunotherapy, University of Birmingham; Institute of Metabolism and Systems Research, University of Birmingham; Institute of Inflammation and Ageing, University of Birmingham; Sandwell and West Birmingham NHS Trust
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2024-04-23
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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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Bishop EL, Gudgeon N, Fulton-Ward T, Stavrou V, Roberts J, Boufersaoui A, Tennant DA, Hewison M, Raza K, Dimeloe S. 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
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