Toker, O. | Search bioRxiv

bioRxiv2022

Enhanced methionine cycle suppresses naïve CD8+ T-cell maturation

The metabolic pathways controlling naive CD8+ T (Tn) cell maturation following thymic egress remain mostly undefined. This is important because immature Tn are a major component of peripheral immune tolerance in newborns and under lymphopenia. In this study we demonstrate that TMRM, a mitochondrial membrane potential marker, could be applied to rapidly identify an immature Tn cell population in the periphery. Applying this marker to perform metabolic and proteomic analysis, we show that immature Tn cells maintain accelerated methionine cycle in respect to mature Tn. This unique metabolic state was associated with restricted Tbx21 locus and diminished immune response in vitro and in vivo. Following our findings, we demonstrate that inhibition of methionine cycle leads to rapid functional maturation of Tn and recovery of immune response to stimuli. Our work provides insight into the way the rate of methionine cycling regulates T cell maturation, opening a path for metabolic manipulation of immune tolerance.

immunology↗

bioRxiv2020

Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix substrate-level phosphorylation arrest

Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions including chronic obstructive pulmonary disease (COPD). However, the influence of SOR on T cell protective immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells. We find that low oxygen diminishes CD8+ T cell viral response in vivo. Using genetic and pharmacological models, we demonstrate that respiratory restriction inhibits ATP dependent matrix processes, all critical for mitochondrial biogenesis. The effect mediated by respiratory restriction could be rescued by TCA cycle re-stimulation, which led to increased mitochondrial matrix localized ATP via substrate-level phosphorylation. Finally, we demonstrate that short exposure to atmospheric oxygen pressure rescues the CD8+ viral response under systemic oxygen restriction in vivo. Our findings reveal the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells and provide a new approach for reducing viral infections in COPD. HighlightsO_LISystemic chronic hypoxia compromises CD8+ T cell activation C_LIO_LIShortly upon activation, T cells cytoplasmic activity becomes independent of mitochondrial ATP outflux C_LIO_LIRespiratory-blockade arrests mitochondrial remodeling due to energy depletion C_LIO_LIUncoupler-based TCA stimulation rescues respiratory-restricted activated CD8+ T cells by stimulating matrix localized substrate-level phosphorylation C_LIO_LICD8+ T cell arrest due to hypoxia in vivo can be rescued by short exposure to atmospheric oxygen pressure. C_LI

immunology↗