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4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8^(+) T cell proliferation 被引量:9
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作者 Beom K Choi Do Y Lee +5 位作者 Don G Lee Young H Kim Seon-Hee Kim Ho S Oh Chungyong Han Byoung S Kwon 《Cellular & Molecular Immunology》 SCIE CAS CSCD 2017年第9期748-757,共10页
4-1BB(CD137)is a strong enhancer of the proliferation of CD8^(+)T cells.Since these cells require increased production of energy and biomass to support their proliferation,we hypothesized that 4-1BB signaling activate... 4-1BB(CD137)is a strong enhancer of the proliferation of CD8^(+)T cells.Since these cells require increased production of energy and biomass to support their proliferation,we hypothesized that 4-1BB signaling activated glucose and fatty acid metabolism.We found that treatment with agonistic anti-4-1BB mAb promoted the proliferation of CD8^(+)T cells in vitro,increasing their size and granularity.Studies with a glycolysis inhibitor and a fatty acid oxidation inhibitor revealed that CD8^(+)T cell proliferation required both glucose and fatty acid metabolism.Anti-4-1BB treatment increased glucose transporter 1 expression and activated the liver kinase B1(LKB1)-AMP-activated protein kinase(AMPK)-acetyl-CoA carboxylase(ACC)signaling pathway,which may be responsible for activating the metabolism of glucose and fatty acids.We also examined whether blocking glucose or fatty acid metabolism affected cell cycle progression and the anti-apoptotic effect of 4-1BB signaling.The increase of anti-apoptotic factors and cyclins in response to anti-4-1BB treatment was completely prevented by treating CD8^(+)T cells with the fatty acid oxidation inhibitor,etomoxir,but not with the glycolysis inhibitor,2-deoxy-D-glucose.We conclude that anti-4-1BB treatment activates glucose and fatty acid metabolism thus supporting the increased demand for energy and biomass,and that fatty acid metabolism plays a crucial role in enhancing the cell cycle progression of anti-CD3-activated CD8^(+)T cells in vitro and the anti-apoptotic effects of 4-1BB signaling on these cells. 展开更多
关键词 AMPK CD8^(+)T cells 4-1BB(CD137) LKB1 METABOLISM
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Chronic activation of 4-1BB signaling induces granuloma development in tumor-draining lymph nodes that is detrimental to subsequent CD8^(+)T cell responses
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作者 Seon-Hee Kim Rohit Singh +10 位作者 Chungyong Han Eunjung Cho Yu I.Kim Don G.Lee Young H.Kim Sang Soo Kim Dong Hoon Shin Hye Jin You Hyeon-Woo Lee Byoung S.Kwon Beom K.Choi 《Cellular & Molecular Immunology》 SCIE CAS CSCD 2021年第8期1956-1968,共13页
The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy.However,the adverse side effects associated with agonist antibodies have hindered their clinical deve... The antitumor capabilities of agonistic anti-4-1BB mAbs have made them an attractive target for tumor immunotherapy.However,the adverse side effects associated with agonist antibodies have hindered their clinical development.Here,we aimed to study the immune-related adverse events of repeated doses and long-term use of agonistic anti-4-1BB mAbs.We show that chronic activation of 4-1BB signals induced the accumulation of IFN-γ-producing PD-1^(+)CD8^(+)T cells in the secondary lymphoid organs of tumor-bearing mice by increasing the number of dividing CD8^(+)T cells,which was beneficial for suppressing tumor growth in the early phase of anti-4-1BB induction.However,repeated exposure to anti-4-1BB mAbs led to granuloma development in tumor-draining lymph nodes(TDLNs)of mice due to recruitment and accumulation of macrophages via the CD8^(+)T cell-IFN-γaxis.This was accompanied by excessive lymph node swelling,which impaired the sequential activation of CD8^(+)T cells.Our data provide insights into the immune-related adverse events of long-term agonist 4-1BB antibody dosing,which should be considered during the clinical development of immunomodulating therapy. 展开更多
关键词 4-1BB COSTIMULATION GRANULOMA CD8 lymphocyte MACROPHAGE
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4-1BB-4-1BBL cis-interaction contributes to the survival of selfreactive CD8^(+)T cell
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作者 Eunjung Cho Rohit Singh +9 位作者 Chungyong Han Seon-Hee Kim Kwang H.Kim Bo-Mi Park Dong Hoon Shin Seongeun Han Young H.Kim Byoung S.Kwon Ki Taek Nam Beom K.Choi 《Cellular & Molecular Immunology》 SCIE CAS CSCD 2023年第9期1077-1080,共4页
4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of... 4-1BB is an inducible receptor expressed on activated T cells,while its ligand,4-1BBL,is mainly expressed in antigen-presenting cells and macrophages[1,2].To the best of our knowledge,ligandmediated transactivation of 4-1BB is responsible for the survival and immune effector functions of T cells. 展开更多
关键词 INTERACTION activation knowledge
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