Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Immunology volume 14, pages 489–499 (2013)Cite this article

Subjects

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The lipid-biosynthesis program of activated T cells is SREBP dependent and sensitive to the PI(3)K-mTOR pathway.
Figure 2: Deletion of Scap inhibits SREBP activity but does not affect T cell homeostasis.
Figure 3: SREBP activity influences the growth and proliferation of CD8+ T cells.
Figure 4: Loss of SREBP signaling affects lipid homeostasis but does not perturb proximal TCR signaling.
Figure 5: SREBP activity influences a transcriptional program related to lipid and RNA metabolism.
Figure 6: SREBP signaling is required for the metabolic reprograming of activated CD8+ T cells.
Figure 7: The addition of cholesterol restores the growth and proliferation of Scap-deficient CD8+ T cells.
Figure 8: Loss of SREBP activity impairs the clonal expansion of antigen-specific effector CD8+ T cells but does not perturb homeostatic proliferation.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. Kim, J.W. & Dang, C.V. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 66, 8927–8930 (2006).

    Article  CAS  Google Scholar 

  2. Fox, C.J., Hammerman, P.S. & Thompson, C.B. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 5, 844–852 (2005).

    Article  CAS  Google Scholar 

  3. Maciver, N.J. 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).

    Article  Google Scholar 

  4. Chen, H.W., Heiniger, H.J. & Kandutsch, A.A. Relationship between sterol synthesis and DNA synthesis in phytohemagglutinin-stimulated mouse lymphocytes. Proc. Natl. Acad. Sci. USA 72, 1950–1954 (1975).

    Article  CAS  Google Scholar 

  5. Rathmell, J.C., Elstrom, R.L., Cinalli, R.M. & Thompson, C.B. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Michalek, R.D. 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).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Geyeregger, R. 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).

    Article  CAS  Google Scholar 

  12. Horton, J.D., Goldstein, J.L. & Brown, M.S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125–1131 (2002).

    Article  CAS  Google Scholar 

  13. Shimomura, I., Shimano, H., Korn, B.S., Bashmakov, Y. & Horton, J.D. 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).

    Article  CAS  Google Scholar 

  14. Yang, K., Neale, G., Green, D.R., He, W. & Chi, H. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat. Immunol. 12, 888–897 (2011).

    Article  CAS  Google Scholar 

  15. Shimano, H. 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).

    Article  CAS  Google Scholar 

  16. Shimano, H. 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).

    Article  CAS  Google Scholar 

  17. Matsuda, M. 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).

    Article  CAS  Google Scholar 

  18. He, H.T., Lellouch, A. & Marguet, D. Lipid rafts and the initiation of T cell receptor signaling. Semin. Immunol. 17, 23–33 (2005).

    Article  CAS  Google Scholar 

  19. Janes, P.W., Ley, S.C., Magee, A.I. & Kabouridis, P.S. The role of lipid rafts in T cell antigen receptor (TCR) signalling. Semin. Immunol. 12, 23–34 (2000).

    Article  CAS  Google Scholar 

  20. Huang, W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

    Article  CAS  Google Scholar 

  21. Huang, W., Sherman, B.T. & Lempicki, R.A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13 (2009).

    Article  Google Scholar 

  22. Dang, C.V., Kim, J.W., Gao, P. & Yustein, J. The interplay between MYC and HIF in cancer. Nat. Rev. Cancer 8, 51–56 (2008).

    Article  CAS  Google Scholar 

  23. Tamás, P. 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).

    Article  Google Scholar 

  24. Levental, I., Grzybek, M. & Simons, K. Greasing their way: lipid modifications determine protein association with membrane rafts. Biochemistry 49, 6305–6316 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  26. Ahmed, R., Salmi, A., Butler, L.D., Chiller, J.M. & Oldstone, M.B. 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).

    Article  CAS  Google Scholar 

  27. Goldrath, A.W., Bogatzki, L.Y. & Bevan, M.J. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J. Exp. Med. 192, 557–564 (2000).

    Article  CAS  Google Scholar 

  28. Freed-Pastor, W.A. et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148, 244–258 (2012).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  34. Tone, Y. 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).

    Article  CAS  Google Scholar 

  35. Wu, M. 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).

    Article  CAS  Google Scholar 

  36. Boren, J. 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).

    CAS  PubMed  Google Scholar 

  37. Brooks, D.G., Teyton, L., Oldstone, M.B. & McGavern, D.B. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J. Virol. 79, 10514–10527 (2005).

    Article  CAS  Google Scholar 

Download references

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

  1. M Benjamin Hock

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

Authors and 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

Authors
  1. Yoko Kidani
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Heidi Elsaesser
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. M Benjamin Hock
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Laurent Vergnes
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Kevin J Williams
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Joseph P Argus
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Beth N Marbois
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Evangelia Komisopoulou
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Elizabeth B Wilson
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Timothy F Osborne
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Thomas G Graeber
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Karen Reue
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. David G Brooks
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Steven J Bensinger
    View author publications

    You can also search for this author inPubMed Google Scholar

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.).

Corresponding author

Correspondence to Steven J Bensinger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Tables 1–2 (PDF 1409 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kidani, Y., Elsaesser, H., Hock, M. et al. Sterol regulatory element–binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 14, 489–499 (2013). https://doi.org/10.1038/ni.2570

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing