OXPHOS promotes apoptotic resistance and cellular persistence in T _H 17 cells in the periphery and tumor microenvironment

Abstract

T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17–producing CD4 T cells (T H 17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. T H 17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that T H 17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates T H 17 processes, such as their ability to persist and thus contribute to protracted immune responses. Here, we modified standardized culture medium and identified a culture system that reliably induces OXPHOS dependence in T H 17s. We found that T H 17s cultured under OXPHOS conditions metabolically resembled their in vivo counterparts, whereas glycolytic cultures were dissimilar. OXPHOS T H 17s exhibited increased mitochondrial fitness, glutamine anaplerosis, and an antiapoptotic phenotype marked by high BCL-XL and low BIM. Limited mitophagy, mediated by mitochondrial fusion regulator OPA-1, was critical to apoptotic resistance in OXPHOS T H 17s. By contrast, glycolytic T H 17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. In addition, through adoptive transfer experiments, we demonstrated that OXPHOS protected T H 17s from apoptosis while enhancing their persistence in the periphery and tumor microenvironment in a murine model of melanoma. Together, our work demonstrates how metabolism regulates T H 17 cell fate and highlights the potential for therapies that target OXPHOS in T H 17-driven diseases.

Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

“…Next, we determined if AR signaling modified mitochondrial morphology by electron microscopy (EM). Mitochondria from Ar Tfm male mice were larger and more numerous compared to mitochondria from WT male mice, showing that AR signaling decreased mitochondrial size and number which has been associated with decreased mitochondrial respiration and Th17 effector function (Figure 3F) (Baixauli et al ., 2022; Buck et al ., 2016; Hong et al ., 2022). Collectively, these data show AR signaling specifically restricts oxidative metabolic output in Th17 cells, though the exact mechanisms and pathways remained unclear.…”

“…These findings, along with previous studies on the importance of mitochondrial dynamics and function in Th17 cells (Baixauli et al ., 2022; Buck et al ., 2016; Hong et al ., 2022) align with our functional findings regarding decreased mitochondrial respiration and qualitative findings regarding changes in the mitochondria. Therefore, it is possible that AR signaling impacts KDM6 mediated H3K27me3 methylation on multiple Th17-related pathways and this can be explored in future studies.…”

“…Th17 cells require de novo fatty acid synthesis (Berod et al, 2014) and one carbon metabolism (Sugiura et al, 2022) for differentiation, effector function, and cytokine expression (Kono, 2022). Pathogenic Th17 cells have recently been shown to rely upon OXPHOS and mitochondrial metabolism (Baixauli et al, 2022; Buck et al, 2016; Hong et al, 2022; Shin et al, 2020). Further, glutaminolysis is essential for Th17 differentiation and effector function, important for Th2 function, and conversely may inhibit Th1 differentiation (Healey et al, 2021; Johnson et al, 2018; Kono, 2022; Kono et al, 2018).…”

Inhibition of the mitochondria-shaping protein Opa1 restores sensitivity to Gefitinib in a lung adenocarcinomaresistant cell line

“…Not surprisingly, Opa1 inhibition using MYLS22, therefore, recapitulates the effects of genetic Opa1 deletion, in PC9M2 cells (here) as well as in endothelial cells and in TNBC cells, and orthotopically implanted tumors [ 18 , 21 ]. MYLS22 has been validated independently as an Opa1 inhibitor that aggravates alveolar cell necroptosis and sensitizes T helper 17 cells to apoptosis [ 37 , 38 ]. Mechanistically, our results corroborate the concept that Opa1 is a key molecule to regulating cytochrome c egress from mitochondria.…”

A Mitochondrial Perspective on Noncommunicable Diseases

“…MiRNAs can regulate the progression of AD by disrupting the mitochondrial membrane integrity to aggravate (miR-16–5p, miR-195, and miR-29b) [ 118 , 119 , 120 ] and inhibiting the activity of OXPHOS-related enzymes’ activity (miR-210, miR-338, and miR-34a) [ 81 , 121 ]. In addition, in AD transgenic mice and rat hippocampal neuronal cells, the silence of miR-204 can alleviate the symptoms of AD by reducing mitochondrial autophagy and ROS production in neurons, thereby [ 122 , 123 ]. In CVDs, Intravenous injection of microRNA-210 blocked the effect and recovered the increased myocardial IR injury and cardiac dysfunction by controlling mitochondrial bioenergy and ROS flux [ 124 ].…”