The TNFα/TNFR2 axis mediates natural killer cell proliferation by promoting aerobic glycolysis  

作　　者：Abrar Ul Haq Khan Alaa Kassim Ali Bryan Marr Donghyeon Jo Simin Ahmadvand Claire Fong-McMaster Saeedah Musaed Almutairi Lisheng Wang Subash Sad Mary-Ellen Harper Seung-Hwan Lee 

机构地区：[1]Department of Biochemistry,Microbiology,and Immunology,Faculty of Medicine,University of Ottawa,Ottawa,ON,Canada [2]The University of Ottawa Centre for Infection,Immunity,and Inflammation,Ottawa,ON,Canada [3]Botany and Microbiology Department,College of Sciences,King Saud University,Riyadh,Saudi Arabia

出　　处：《Cellular & Molecular Immunology》2023年第10期1140-1155,共16页中国免疫学杂志（英文版）

摘　　要：Natural killer(NK)cells are predominant innate lymphocytes that initiate the early immune response during infection.NK cells undergo a metabolic switch to fuel augmented proliferation and activation following infection.Tumor necrosis factor-alpha(TNFα)is a well-known inflammatory cytokine that enhances NK cell function;however,the mechanism underlying NK cell proliferation in response to TNFαis not well established.Here,we demonstrated that upon infection/inflammation,NK cells upregulate the expression of TNF receptor 2(TNFR2),which is associated with increased proliferation,metabolic activity,and effector function.Notably,IL-18 can induce TNFR2 expression in NK cells,augmenting their sensitivity toward TNFα.Mechanistically,TNFα-TNFR2 signaling upregulates the expression of CD25(IL-2Rα)and nutrient transporters in NK cells,leading to a metabolic switch toward aerobic glycolysis.Transcriptomic analysis revealed significantly reduced expression levels of genes involved in cellular metabolism and proliferation in NK cells from TNFR2 KO mice.Accordingly,our data affirmed that genetic ablation of TNFR2 curtails CD25 upregulation and TNFα-induced glycolysis,leading to impaired NK cell proliferation and antiviral function during MCMV infection in vivo.Collectively,our results delineate the crucial role of the TNFα-TNFR2 axis in NK cell proliferation,glycolysis,and effector function.

关 键 词：Natural killer cells TNFA TNFR2 GLYCOLYSIS PROLIFERATION Murine cytomegalovirus 

分 类 号：R392[医药卫生—免疫学]