Fatty acid oxidation fuels natural killer cell responses against infection and cancer

• 成果类型: Article
• 署名作者: Sheppard, Sam; Srpan, Katja; Lin, Wendy; Lee, Mariah; Delconte, Rebecca B.; Owyong, Mark; Carmeliet, Peter; Davis, Daniel M.; Xavier, Joao B.; Hsu, Katharine C.; Sun, Joseph C.
• 署名单位: Memorial Sloan Kettering Cancer Center; Imperial College London; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; KU Leuven; KU Leuven
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8652
• DOI: 10.1073/pnas.2319254121
• 发表日期: 2024-03-12
• 关键词: cd8(+) t-cells; cytomegalovirus; RECOGNITION; activation; prerequisite; metabolism; carnitine; mouse; mice

摘要

Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long - chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A- deficient NK cells. Furthermore, CPT1A- deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.