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

• DOI: 10.1126/scisignal.adg5678
• Publication Date: 2024-04-23T17:58:50Z
• Authors: Emma L. Bishop; Nancy Gudgeon; Taylor Fulton-Ward; Victoria Stavrou; Jennie Roberts; Adam Boufersaoui; Daniel A. Tennant; Martin Hewison; Karim Raza; Sarah Dimeloe
• Keywords: Arthritis, Rheumatoid; CD4-Positive T-Lymphocytes; 0303 health sciences; 03 medical and health sciences; Tumor Necrosis Factor-alpha; Metabolic Reprogramming; TOR Serine-Threonine Kinases; Humans; Cell Differentiation; Proto-Oncogene Proteins c-akt; Signal Transduction; Mitochondria

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.