Functional and metabolic fitness of human CD4+ T lymphocytes during metabolic stress.

Ezio Bonifacio,Anette-Gabriele Ziegler,Daniel Brandt,Virag Sharma,Lisa Holthaus,Martin Jastroch

doi:10.26508/lsa.202101013

Abstract

Human CD4+ T cells are essential mediators of immune responses. By altering the mitochondrial and metabolic states, we defined metabolic requirements of human CD4+ T cells for in vitro activation, expansion, and effector function. T-cell activation and proliferation were reduced by inhibiting oxidative phosphorylation, whereas early cytokine production was maintained by either OXPHOS or glycolytic activity. Glucose deprivation in the presence of mild mitochondrial stress markedly reduced all three T-cell functions, contrasting the exposure to resveratrol, an antioxidant and sirtuin-1 activator, which specifically inhibited cytokine production and T-cell proliferation, but not T-cell activation. Conditions that inhibited T-cell activation were associated with the down-regulation of 2',5'-oligoadenylate synthetase genes via interferon response pathways. Our findings indicate that T-cell function is grossly impaired by stressors combined with nutrient deprivation, suggesting that correcting nutrient availability, metabolic stress, and/or the function of T cells in these conditions will improve the efficacy of T-cell-based therapies.

Highlights

T cells are quiescent surveillants that can rapidly transform into proliferative effector T cells to target pathogens or anomalous expression of self-proteins
Mitochondrial oxidative phosphorylation (OXPHOS) is generally associated with resting and activated T-cell states and glucose metabolism is associated with the effector T-cell functions
Human CD4+ T cells were first monitored after stimulation with anti-CD3/CD28 beads in the presence of 5 mM of glucose to define the activation phase as the first 16 h post-stimulation, and the transition phase to proliferation as 16–72 h post-stimulation (Fig S1A and B)

Summary

Introduction

T cells are quiescent surveillants that can rapidly transform into proliferative effector T cells to target pathogens or anomalous expression of self-proteins. This transition is tightly controlled at the signaling and metabolic levels. The T-cell quiescent state is defined by low metabolic, transcriptional, and translational activity (Yang et al, 2011; Chapman et al, 2020). Resting T cells are defined by low metabolic demands, a reliance on oxidative phosphorylation (OXPHOS)–derived ATP, and suppression of glycolysis (O’Neill et al, 2016; Chapman et al, 2020)

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