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

Area of Science:

• Immunology
• Metabolism
• Cellular senescence

Background:

• Mitochondrial health and cellular metabolism influence T cell senescence.
• CD8+ EMRA T cells show mitochondrial dysfunction and altered oxidative phosphorylation.
• Metabolic properties of senescent CD8+ T cells in type 2 diabetes (T2D) are unknown.

Purpose of the Study:

• To investigate the metabolic characteristics of senescent CD8+ T cells in individuals with T2D.
• To understand the impact of T2D on T cell mitochondrial function and metabolism.

Main Methods:

• Comparative analysis of mitochondrial function in CD8+ T cells from T2D patients and age-matched controls.
• Assessment of mitochondrial reactive oxygen species (mtROS), fatty acid uptake and oxidation, lipid droplet accumulation, and AMPK activity.
• Experimental manipulation of glucose and fatty acid levels in healthy CD8+ T cells.

Main Results:

• T2D CD8+ T cells exhibit higher mitochondrial oxidative capacity and increased mtROS compared to controls.
• Impaired fatty acid oxidation, increased fatty acid uptake, lipid droplet accumulation, and decreased AMPK activity were observed in T2D CD8+ T cells.
• In vitro exposure of healthy CD8+ T cells to high glucose and fatty acids induced p-p53 expression and mitochondrial fragmentation, mimicking T2D T cell phenotype.

Conclusions:

• Type 2 diabetes induces significant mitochondrial dysfunction and metabolic alterations in CD8+ T cells.
• These metabolic abnormalities, including increased mtROS and impaired fatty acid oxidation, likely impact T cell function.
• Targeting these metabolic pathways offers a potential strategy to restore T cell function and mitigate T2D-related immune dysfunction.