INTERLEUKIN 21-INDUCED METABOLIC REPROGRAMMING DRIVES CD4 T CELL INFLAMMATORY RESPONSE DURING INTESTINAL INFLAMMATION

Significant proportion of inflammatory bowel disease (IBD) patients continue to respond inconsistently therapies, underscoring complexity and the need for efficacious treatment. Interleukin 21 (IL-21), which is known support T helper (Th) cell function, highly expressed within inflamed tissues IBD compared healthy controls. Also, regulatory cells (Tregs) have been linked refractory human IBD, complete induction in mice has shown require IL-21. Given that Tregs are critical self-tolerance prevention we investigated metabolic role IL-21 instigating Treg dysfunction therapeutic ramifications targeting pathways during IBD. Human as well relevant control Th were generated from naïve CD4+ isolated blood donors. Microarray analysis was utilized targeted transcriptional profiling. Immune phenotyping assessed by fluorescence-activated sorting. Metabolic Seahorse flux mass spectrometry-based metabolomics. Colitis induced Rag1-/- (T B deficient) adoptive transfer pathogenic cells. Acute stimulation glycolysis fluctuations mitochondrial respiration (i.e. oxidative phosphorylation – OXPHOS), analysis. In agreement, microarray analysis, validated qPCR, revealed IL-21-induced alterations expression genes associated with OXPHOS metabolism. Prolonged rendered susceptible response, evidenced production cytokines such interferon γ, tumor necrosis factor, IL-17A, IL-17F. Exploring mechanisms underlying effects, observed reduced inactive glycogen synthase kinase 3 (GSK3) β, a protein prevent pyruvate entry into mitochondria. This reduction GSK3β response accompanied high abundance intracellular lactate, Importantly, GSK3 inhibition or exogenous membrane-permeable methyl abrogated rewiring response. Moreover, diminished function Lastly, prevented cell-induced colitis mice, Disease Activity Index, Mouse Colon Histology serum cytokines. potently engages state subsequently augments an phenotype. Therefore, desensitizing detrimental cues, IL-21, may augment