Effects of Limiting Citrate-Derived Acetyl-CoA Synthesis on Exhaustion in CD8 T Cells

Overview

T cell exhaustion is a hypofunctional fate observed in cancer that causes loss of full mitochondrial function. Preventing T cell exhaustion could sustain the immune system’s anti-tumor response. An accumulation of lipid droplets in exhausted T cells has been observed, suggesting that metabolic insufficiency results in alternative carbon utilization and raising the question of how lipid synthesis might be related to the progression of T cells toward exhaustion. I investigated the impact of limiting intracellular citrate-derived Acetyl-CoA production on the development of T cell exhaustion by targeting ATP-citrate lyase (ACLY), which converts citrate to Acetyl-CoA. CD8⁺ T cells from C57Bl/6 mice were activated for 24 hours through the T cell receptor (TCR) in vitro. Cells either received no additional stimulation (acute stimulation, AS) or continuous TCR stimulation for 6 days (chronic stimulation, CS). Within each AS/CS group, cells were treated with ACLY inhibitor (ACLYi) concentrations of 0µM, 10µM, 20µM, or 40µM per subgroup. Cells were analyzed by flow cytometry for markers of exhaustion. In both AS and CS conditions, a greater amount of pro-inflammatory cytokines were produced by cells treated with 40µM ACLYi than cells treated with lower concentrations. CS cells were most impacted: 5.39% of cells without ACLYi were IFNγhi TNF-αhi, compared to 51.0% with 40µM ACLYi. No notable difference in PD-1 or TIM-3 expression was observed in any cell group. These data suggest that ACLY inhibition preserves T cell effector function under chronic stimulation conditions. Additional experimentation can be done to identify the most optimal ACLYi concentration. Future steps also include repeat testing under hypoxia and in vivo experimentation with tumor-bearing mice.

Competition history

• AJAS 2024 Category not listed

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