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Sterol regulatory element–binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity

Nature Immunology volume 14, pages 489499 (2013) | Download Citation

Abstract

Newly activated CD8+ T cells reprogram their metabolism to meet the extraordinary biosynthetic demands of clonal expansion; however, the signals that mediate metabolic reprogramming remain poorly defined. Here we demonstrate an essential role for sterol regulatory element–binding proteins (SREBPs) in the acquisition of effector-cell metabolism. Without SREBP signaling, CD8+ T cells were unable to blast, which resulted in attenuated clonal expansion during viral infection. Mechanistic studies indicated that SREBPs were essential for meeting the heightened lipid requirements of membrane synthesis during blastogenesis. SREBPs were dispensable for homeostatic proliferation, which indicated a context-specific requirement for SREBPs in effector responses. Our studies provide insights into the molecular signals that underlie the metabolic reprogramming of CD8+ T cells during the transition from quiescence to activation.

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References

  1. 1.

    & Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 66, 8927–8930 (2006).

  2. 2.

    , & Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5, 844–852 (2005).

  3. 3.

    et al. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J. Leukoc. Biol. 84, 949–957 (2008).

  4. 4.

    , & Relationship between sterol synthesis and DNA synthesis in phytohemagglutinin-stimulated mouse lymphocytes. Proc. Natl. Acad. Sci. USA 72, 1950–1954 (1975).

  5. 5.

    , , & Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur. J. Immunol. 33, 2223–2232 (2003).

  6. 6.

    et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 185, 1037–1044 (2010).

  7. 7.

    et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

  8. 8.

    et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134, 97–111 (2008).

  9. 9.

    et al. Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc. Natl. Acad. Sci. USA 108, 18348–18353 (2011).

  10. 10.

    & Interrelationships between mevalonate metabolism and the mitogenic signaling pathway in T lymphocyte proliferation. J. Biol. Chem. 266, 12216–12222 (1991).

  11. 11.

    et al. Liver X receptors interfere with cytokine-induced proliferation and cell survival in normal and leukemic lymphocytes. J. Leukoc. Biol. 86, 1039–1048 (2009).

  12. 12.

    , & SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

  13. 13.

    , , , & Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J. Biol. Chem. 273, 35299–35306 (1998).

  14. 14.

    , , , & The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat. Immunol. 12, 888–897 (2011).

  15. 15.

    et al. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J. Clin. Invest. 98, 1575–1584 (1996).

  16. 16.

    et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J. Clin. Invest. 100, 2115–2124 (1997).

  17. 17.

    et al. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15, 1206–1216 (2001).

  18. 18.

    , & Lipid rafts and the initiation of T cell receptor signaling. Semin. Immunol. 17, 23–33 (2005).

  19. 19.

    , , & The role of lipid rafts in T cell antigen receptor (TCR) signalling. Semin. Immunol. 12, 23–34 (2000).

  20. 20.

    , & Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

  21. 21.

    , & Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13 (2009).

  22. 22.

    , , & The interplay between MYC and HIF in cancer. Nat. Rev. Cancer 8, 51–56 (2008).

  23. 23.

    et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203, 1665–1670 (2006).

  24. 24.

    , & Greasing their way: lipid modifications determine protein association with membrane rafts. Biochemistry 49, 6305–6316 (2010).

  25. 25.

    et al. Transcriptional regulation of phagocytosis-induced membrane biogenesis by sterol regulatory element binding proteins. Proc. Natl. Acad. Sci. USA 102, 13129–13134 (2005).

  26. 26.

    , , , & Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160, 521–540 (1984).

  27. 27.

    , & Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557–564 (2000).

  28. 28.

    et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148, 244–258 (2012).

  29. 29.

    et al. EGFR signaling through an Akt-SREBP-1-dependent, rapamycin-resistant pathway sensitizes glioblastomas to antilipogenic therapy. Sci. Signal. 2, ra82 (2009).

  30. 30.

    et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

  31. 31.

    et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

  32. 32.

    et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

  33. 33.

    et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

  34. 34.

    et al. OX40 gene expression is up-regulated by chromatin remodeling in its promoter region containing Sp1/Sp3, YY1, and NF-κB binding sites. J. Immunol. 179, 1760–1767 (2007).

  35. 35.

    et al. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am. J. Physiol. Cell Physiol. 292, C125–C136 (2007).

  36. 36.

    et al. Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. J. Biol. Chem. 276, 37747–37753 (2001).

  37. 37.

    , , & Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J. Virol. 79, 10514–10527 (2005).

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Acknowledgements

We thank Y. Tone and M. Tone (Cedars-Sinai Medical Center) for retroviral vector MIGR1; T. Osborne (Sanford-Burnham Medical Research Institute) for polyclonal antibody to SREBP1 or SREBP2; A. Do, L. Pang, A. Armijo and C. Radu for technical assistance; and P. Tontonoz and M. Day for critical feedback on the manuscript. Supported by the US National Institutes of Health (AI093768 to S.J.B., and AI082975 and AI085043 to D.G.B.), the Jonsson Comprehensive Cancer Center Foundation of the University of California, Los Angeles (S.J.B. and Y.K.), the National Center for Research Resources (S10RR026744 to L.V. and K.R.), the National Cancer Institute of the US National Institutes of Health (T32-CA009120-36 to K.J.W.), the US Public Health Service (T32-GM008469 to J.P.A.) and the University of California, Los Angeles, Graduate Division (J.P.A.).

Author information

Author notes

    • M Benjamin Hock

    Present address: Amgen, Thousand Oaks, California, USA.

Affiliations

  1. Institute for Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Yoko Kidani
    • , M Benjamin Hock
    • , Kevin J Williams
    • , Joseph P Argus
    • , Beth N Marbois
    • , Thomas G Graeber
    •  & Steven J Bensinger
  2. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Yoko Kidani
    • , M Benjamin Hock
    • , Kevin J Williams
    •  & Steven J Bensinger
  3. Department of Microbiology, Immunology, & Molecular Genetics, and the UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Heidi Elsaesser
    • , Elizabeth B Wilson
    •  & David G Brooks
  4. Department of Human Genetics, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, California, USA.

    • Laurent Vergnes
    •  & Karen Reue
  5. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Joseph P Argus
    • , Evangelia Komisopoulou
    • , Thomas G Graeber
    •  & Steven J Bensinger
  6. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California, USA.

    • Beth N Marbois
  7. Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Evangelia Komisopoulou
    •  & Thomas G Graeber
  8. Metabolic Signaling and Disease Program, Diabetes and Obesity Center, Sanford-Burnham Medical Research Institute, Orlando, Florida, USA.

    • Timothy F Osborne
  9. Department of Medicine, David Geffen School of Medicine, and the Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.

    • Karen Reue

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Contributions

Y.K. designed, did and analyzed most of the experiments and wrote the manuscript; H.E., M.B.H., L.V., K.J.W., J.P.A., B.N.M., E.K. and E.B.W. did experiments and analyzed data; T.F.O. provided materials and intellectual input; and S.J.B. provided overall coordination for the conception, design and supervision of the study and wrote the manuscript (with input from T.F.O., T.G.G., K.R. and D.G.B.).

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Steven J Bensinger.

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DOI

https://doi.org/10.1038/ni.2570

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