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

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-alpha (TNF-alpha) released by human na & iuml;ve 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-alpha were mediated by activation of Akt-mTOR signaling by the kinase ITK and did not require the NF-kappa B pathway. TNF-alpha stimulated the differentiation of na & iuml;ve 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-alpha 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-alpha drives their metabolic reprogramming by promoting signaling through ITK, Akt, and mTOR, which is dysregulated in autoinflammatory disease.