Fatty Acid Synthase Contributes to Restimulation-Induced Cell Death of Human CD4 T Cells.

Kelsey Voss,Katherine Pohida,Christopher R Luthers,Andrew L Snow

doi:10.3389/fmolb.2019.00106

Kelsey Voss, Katherine Pohida + Show 2 more

Open Access

https://doi.org/10.3389/fmolb.2019.00106

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Abstract

Restimulation-induced cell death (RICD) is an apoptotic pathway triggered in activated effector T cells after T cell receptor (TCR) re-engagement. RICD operates at the peak of the immune response to ensure T cell expansion remains in check to maintain immune homeostasis. Understanding the biochemical regulation of RICD sensitivity may provide strategies for tuning the magnitude of an effector T cell response. Metabolic reprogramming in activated T cells is not only critical for T cell differentiation and effector functions, but also influences apoptosis sensitivity. We previously demonstrated that aerobic glycolysis correlates with optimum RICD sensitivity in human effector CD8 T cells. However, metabolic programming in CD4 T cells has not been investigated in this context. We employed a pharmacological approach to explore the effects of fatty acid and glycolytic metabolism on RICD sensitivity in primary human CD4 T cells. Blockade of fatty acid synthase (FASN) with the compound C75 significantly protected CD4 effector T cells from RICD, suggesting that fatty acid biosynthesis contributes to RICD sensitivity. Interestingly, sphingolipid synthesis and fatty acid oxidation (FAO) were dispensable for RICD. Disruption of glycolysis did not protect CD4 T cells from RICD unless glyceraldehyde-3-phosphate dehydrogenase (GAPDH) enzymatic activity was targeted specifically, highlighting important differences in the metabolic control of RICD in effector CD4 vs. CD8 T cell populations. Moreover, C75 treatment protected effector CD4 T cells derived from naïve, effector memory, and central memory T cell subsets. Decreased RICD in C75-treated CD4 T cells correlated with markedly reduced FAS ligand (FASL) induction and a Th2-skewed phenotype, consistent with RICD-resistant CD4 T cells. These findings highlight FASN as a critical metabolic potentiator of RICD in human effector CD4 T cells.

Highlights

Dynamic metabolic reprogramming propels the rapid proliferation of activated T cells, ensuring clonal expansion is robust enough to eliminate pathogens or tumor cells
Given that effector T cell metabolism is analogous to rapidly dividing cancerous cells, we felt that it was important to examine the impact of this inhibitor (C75) in particular on T cell homeostasis
C75-mediated Restimulation-induced cell death (RICD) resistance could enhance anti-tumor immunity by sparing more terminallydifferentiated cytotoxic effector T cells from apoptosis. This could be potentially beneficial for emerging adoptive T cell therapies as well; e.g., chimeric antigen receptor (CAR) T cells could be rendered more durable upon pre-treatment with C75 in order to survive sustained repeated T cell receptor (TCR) stimulation

Summary

Introduction

Dynamic metabolic reprogramming propels the rapid proliferation of activated T cells, ensuring clonal expansion is robust enough to eliminate pathogens or tumor cells. Upon initial antigen encounter with proper co-stimulation, activated T cells ramp up their anabolic metabolism resulting in increased Krebs cycle activity, oxidative phosphorylation (OXPHOS), and aerobic glycolysis (Pearce, 2010). This “Warburg effect” is presumed to support the production of energy and macromolecular intermediates that enable the swift cell division (Ghesquiere et al, 2014). CD4 T cells rely on the uptake of amino acids like glutamine, arginine and leucine to fuel proliferation, whereas glycolysis may be more important for differentiation and effector functions (e.g., cytokine production) (Buck et al, 2015; Palmer et al, 2015). Inhibitors of metabolic pathways (e.g., Krebs cycle inhibitor LW6) have shown the potential to be potent immunosuppressive drugs (Eleftheriadis et al, 2017)

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