Altered Nutrient Uptake Causes Mitochondrial Dysfunction in Senescent CD8+ EMRA T Cells During Type 2 Diabetes.

Lauren A Callender,Sian M Henson,Elizabeth C Carroll,Desiree Campbell-Richards,Victoria Berryman,Conor Garrod-Ketchley,Melanie Pattrick,Johannes Schroth,Sarah Finer,Gillian A Hood,Graham A Hitman,Jonas Bystrom

doi:10.3389/fragi.2021.681428

Abstract

Mitochondrial health and cellular metabolism can heavily influence the onset of senescence in T cells. CD8+ EMRA T cells exhibit mitochondrial dysfunction and alterations to oxidative phosphorylation, however, the metabolic properties of senescent CD8+ T cells from people living with type 2 diabetes (T2D) are not known. We show here that mitochondria from T2D CD8+ T cells had a higher oxidative capacity together with increased levels of mitochondrial reactive oxgen species (mtROS), compared to age-matched control cells. While fatty acid uptake was increased, fatty acid oxidation was impaired in T2D CD8+ EMRA T cells, which also showed an accumulation of lipid droplets and decreased AMPK activity. Increasing glucose and fatty acids in healthy CD8+ T cells resulted in increased p-p53 expression and a fragmented mitochondrial morphology, similar to that observed in T2D CD8+ EMRA T cells. The resulting mitochondrial changes are likely to have a profound effect on T cell function. Consequently, a better understanding of these metabolic abnormalities is crucial as metabolic manipulation of these cells may restore correct T cell function and help reduce the impact of T cell dysfunction in T2D.

Highlights

Senescent T cells have been implicated in a number of different chronic inflammatory diseases, such as cancer (Zelle-Rieser et al, 2016), obesity (Shirakawa et al, 2016) and rheumatoid arthritis (Weyand et al, 2014)
The cell surface markers CD45RA, CD28, CD27, CCR7 and KLRG1 were used to quantify the frequency of CD8+ T cell subsets in people living with Type 2 Diabetes (T2D) compared with healthy agematched controls and young participants
UMAP analysis indicate that older people living with T2D have an elevated expression of the senescent EMRA T cell subset

Summary

Introduction

Senescent T cells have been implicated in a number of different chronic inflammatory diseases, such as cancer (Zelle-Rieser et al, 2016), obesity (Shirakawa et al, 2016) and rheumatoid arthritis (Weyand et al, 2014). The responses of these T cells are typically slower and of a lower magnitude than those of healthy individuals; whether the response is measured by proliferation (Goronzy and Weyand, 2017), telomerase activity (Patrick and Weng, 2019) or the induction of signalling events (Mold et al, 2019). These studies show an association between T2D and terminally differentiated T cells

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