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. 2024 Nov 19:734:150738.
doi: 10.1016/j.bbrc.2024.150738. Epub 2024 Sep 24.

Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion

Min Liu  1 , Xinyue Fu  1 , Qinghe Yi  1 , Enhong Xu  1 , Longbao Dong  2
Affiliations

Impaired mitochondrial oxidative phosphorylation induces CD8+ T cell exhaustion

Min Liu et al. Biochem Biophys Res Commun. .

Abstract

CD8+ T cells play a crucial role in anti-tumor immunity, but their function can be impaired by exhaustion induced by prolonged antigen stimulation. Mitochondrial dysfunction, a hallmark of the tumor microenvironment (TME), has been linked to various pathologies, but its specific role in CD8+ T cell exhaustion remains underexplored. Here, we established an in vitro model of CD8+ T cell exhaustion by co-culturing OVA-specific OT1 CD8+ T cells with OVA-expressing MC38 tumor cells. Next, we investigated the impact of mitochondrial dysfunction on exhaustion using pharmacological inhibitors targeting the electron transport chain. The role of the mitochondrial complex I component NDUFA10 was further examined through genetic knockout in CD8+ T cells using CRISPR-Cas9. Inhibition of the mitochondrial electron transport chain significantly accelerated CD8+ T cell exhaustion in vitro. Knockout of NDUFA10 in CD8+ T cells led to enhanced tumor growth and increased exhaustion of tumor-infiltrating CD8+ T cells in a Rag1-/- tumor-bearing transfer model. This study highlights the critical role of mitochondrial function in regulating CD8+ T cell exhaustion and anti-tumor activity, providing new insights into the metabolic underpinnings of immune dysfunction in cancer.

Keywords: CD8(+) T cell; Exhaustion; Mitochondrion.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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