Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation

Abstract

Objective Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lymphocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment. Methods Synovial and blood CD4+ T cells isolated ex vivo from patients with juvenile idiopathic arthritis (JIA) and murine CD4+ T cells were either stimulated once or stimulated repeatedly. Their dependency on particular metabolic pathways for survival was then analyzed using pharmacologic inhibitors. The role of the transcription factor Twist 1 was investigated by determining lactate production and oxygen consumption in Twist1‐sufficient and Twist1‐deficient murine T cells. The dependency of these murine cells on particular metabolic pathways was analyzed using pharmacologic inhibitors. Results Programmed death 1 (PD‐1)+ T helper cells in synovial fluid samples from patients with JIA survived via fatty acid oxidation (mean ± SEM survival of 3.4 ± 2.85% in the presence of etomoxir versus 60 ± 7.08% in the absence of etomoxir on day 4 of culture) (P < 0.0002; n = 6) and expressed the E‐box–binding transcription factor TWIST1 (2–14‐fold increased expression) (P = 0.0156 versus PD‐1− T helper cells; n = 6). Repeatedly restimulated murine T helper cells, which expressed Twist1 as well, needed Twist1 to survive via fatty acid oxidation. In addition, Twist1 protected the cells against reactive oxygen species. Conclusion Our findings indicate that TWIST1 is a master regulator of metabolic adaptation of T helper cells to chronic inflammation and a target for their selective therapeutic elimination.

Antigen‐driven PD‐1+TOX+BHLHE40+ and PD‐1+TOX+EOMES+ T lymphocytes regulate juvenile idiopathic arthritis in situ

“…S7A). TWIST1 is selectively upregulated in CD4 + T cells upon repeated antigenic stimulation and enhances expression of genes promoting the persistence of the cells in the inflammatory environment [61–63]. Thirty‐four of the 41 synovial Tcon that expressed TWIST1 belonged to cluster 1 (Fig.…”

Antigen-driven PD-1+TOX+EOMES+ and PD-1+TOX+BHLHE40+ synovial T lymphocytes regulate chronic inflammation in situ

“…7a). TWIST1 is selectively upregulated in CD4 + T cells upon repeated antigenic stimulation and enhances expression of genes promoting persistence of the cells 25,26,97 . 34 of 41 synovial Tcon that expressed TWIST1 , belonged to cluster 1 (Fig.…”

Effect of Increased Lactate Dehydrogenase A Activity and Aerobic Glycolysis on the Proinflammatory Profile of Autoimmune CD8+ T Cells in Rheumatoid Arthritis

“…RA CD4+ T cells use glucose to feed an overactive PPP and accumulate intracellular lipids, thus improving their migration potential and reducing the levels of oxygen radicals, such as reactive oxygen species (ROS), that are required for tolerance induction and activation of ATM kinase, leading to a proinflammatory phenotype (17,18). Moreover, in juvenile arthritis, proinflammatory synovial PD1+CD4+ T cells require TWIST1-regulated fatty acid oxidation for survival in an environment of hypoxia (19).…”