Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis

Abstract

Integration of signaling and metabolic pathways enables and sustains lymphocyte function. While metabolic changes occurring during T cell activation are well-characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. Here we defined the bioenergetics of TH17 effector cells generated in vivo. These cells depend on OXPHOS2 for energy and cytokine production. Mechanistically, the essential role of OXPHOS in TH17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human TH17 cells, including those isolated from Crohn’s disease patients, and is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in TH17 driven diseases.

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

“…The observed metabolic changes (i.e., up-regulated glycolytic and down-regulated TCA cycle activity leading to consequent reduction in inflammatory cytokine production and anergy) are best explained by the observed H3K27-mediated silencing of key transcription factors, such as MYC, PPARγ, and PPRC1, as a consequence of GSK-J4 treatment (63). Recently, it has been shown that inhibition of mTORC1 signaling rescues ATF4deficient cells from MYC-induced endoplasmic reticulum stress (64).…”

Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism

“…The observed metabolic changes-i.e. upregulated glycolytic and downregulated TCA cycle activity leading to consequent reduction in inflammatory cytokine production and anergy- are best explained by the observed H3K27 mediated silencing of key transcription factors such as MYC, PPARg and PPRC1 as a consequence of GSK-J4 treatment (61). Recently, it has been shown that inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress (60).…”

Mitochondrial Oxidative Phosphorylation Regulates the Fate Decision between Pathogenic Th17 and Regulatory T Cells

“…Hence, we reasoned that this fundamental process is critical for the biology of Th17 cells. Previous studies report that fully differentiated Th17 cells showed increased mitochondrial respiration in comparison to naive CD4 T cells (Franchi et al, 2017;Gerriets et al, 2015). However, it is unknown whether mitochondrial OXPHOS is induced during the process of Th17 lineage commitment.…”