title: 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+T cell proliferation.
abstract: 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.
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.|Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Do Y
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.
authors.forename: Don G
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Immune Cell Production Unit, Program for Immunotherapeutic Research, National Cancer Center, Gyeonggi 10408, Korea.
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.
authors.forename: Ho S
authors.initials: HS
authors.lastname: Oh
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.
authors.forename: Chungyong
authors.initials: C
authors.lastname: Han
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi 10408, Korea.|Eutilex, Catholic University School of Medicine, Seoul 06591, Korea.|Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002469:Cell Separation; D048429:Cell Size; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D015398:Signal Transduction; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000103:Acetyl-CoA Carboxylase; D005947:Glucose; D002118:Calcium