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4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation

Cellular & Molecular Immunology volume 14, pages 748–757 (2017)Cite this article

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.

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Acknowledgements

This work was funded by grants from the National Cancer Center of Korea (NCC-1310430), the National Research Foundation of Korea (NRF-2005-0093837, NRF-2013R1A1A2008703), the Korea Drug Development Fund (KDDF-201408-11) and the Ministry of Trade, Industry and Energy of Korea (GLOBAL R&D PROJECT, N0000901).

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Author notes

  1. Beom K Choi and Do Y Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Biology, Cancer Immunology Branch, National Cancer Center, Goyang, 10408, Gyeonggi, Korea

    Beom K Choi, Do Y Lee, Don G Lee, Seon-Hee Kim, Ho S Oh, Chungyong Han & Byoung S Kwon

  2. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 120-752, Korea

    Do Y Lee

  3. Immune Cell Production Unit, Program for Immunotherapeutic Research, National Cancer Center, 10408, Gyeonggi, Korea

    Young H Kim

  4. Eutilex, Catholic University School of Medicine, Seoul, 06591, Korea

    Byoung S Kwon

  5. Department of Medicine, Tulane University Health Sciences Center, New Orleans, 70112, LA, USA

    Byoung S Kwon

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  1. Beom K Choi
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Choi, B., Lee, D., Lee, D. et al. 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation. Cell Mol Immunol 14, 748–757 (2017). https://doi.org/10.1038/cmi.2016.02

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