Year: 2023
Type: conference-abstract
Abstract: Mitochondria utilize various substrates for energy production and intermediatory metabolism to support cellular activities. Cytotoxic CD8 T cells in different functional states during the life cycle have distinct metabolic requirements, and they experience dynamic changes in energy sources and oxygen levels in different microenvironments. The significance of mitochondrial metabolic flexibility for CD8 cell immune responses remains poorly understood. Here we report that the deletion or pharmacological inhibition of PTPMT1, a mitochondria-based phosphatase, significantly decreased effector cell specification and clonal expansion from activated CD8 cells. In addition, PTPMT1 deletion accelerated CD8 T cell exhaustion and impaired stem-like T cell maintenance, leading to increased tumor growth. PTPMT1 depletion also suppressed CD8 T cell anti-viral responses. Mechanistically, the loss of PTPMT1 critically altered mitochondrial fuel selection – the utilization of pyruvate, a major mitochondrial substrate derived from glucose (the simple carbohydrate), was inhibited whereas fatty acid and glutamate utilizations were enhanced. Persistent mitochondrial substrate shift and metabolic inflexibility induced oxidative stress and apoptosis in PTPMT1 knockout CD8 cells. The impact of the biased mitochondrial fuel selection on CD8 T cells was further verified in mitochondrial pyruvate carrier/transporter (MPC) knockout and pharmacological inhibition models. Collectively, this study reveals an important role of PTPMT1 in facilitating mitochondrial utilization of carbohydrates and that mitochondrial flexibility in energy source selection is critical for CD8 T cell anti-tumor immunity. National Institutes of Health grants HL162725 and CA275964
Source: The Journal of Immunology
Authors: Chao Chen, Cheng-Kui Qu
Institution: Emory University
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4385687540