Search tips
Search criteria 


Logo of f1000bioLatest ContentReportsReportsReports
F1000 Biol Rep. 2012; 4: 9.
Published online 2012 May 2. doi:  10.3410/B4-9
PMCID: PMC3342832

The immune diet: meeting the metabolic demands of lymphocyte activation


During the adaptive immune response, lymphocytes undergo dramatic changes in metabolism that accompany the proliferative burst and differentiation into functional subsets. This brief overview focuses on recent advances in understanding the mechanisms of this metabolic reprogramming in T lymphocytes.


The adaptive immune response of vertebrates occurs through clonal selection, an elegant process that involves large numbers of lymphocytes. Each lymphocyte bears a randomly generated receptor that, if bound by its ligand in an appropriate context (indicative of potential infection), stimulates the cell to proliferate, thereby generating many more cells with this receptor. Because the specific cells are pre-selected to remove those that might recognize “self” components, the ligands that might engage the receptors are “foreign” and, thus, may identify an invading organism and orchestrate a response. The responding cells proliferate and functionally differentiate, and ultimately clear the invader. The numbers of responding cells then decline, ultimately leaving memory cells capable of a recall response should the foreign ligands reappear.

The evolution of the adaptive immune response to many pathogens is sometimes viewed as a sort of “arms race,” since the invading organism may have the potential to replicate much more rapidly than the lymphocytes that would control it. It is perhaps not surprising, then, that activated lymphocytes (B and T cells) have one of the shortest cell cycles seen in mature vertebrate animals, replicating every four to six hours [1]. However, this proliferative burst is preceded by a lag phase of about 24 hours, during which the cell grows (increases mass) prior to the first cell cycle entry. As we will see, this lag may be essential for the proliferative burst and for subsequent function of the clones, and the events surrounding these changes represent an emerging area of intense interest.

Preparing T cell metabolism for proliferation

In shifting from a small, resting cell to a rapidly cycling cell, a naïve lymphocyte effectively “reprograms” its metabolism, changing from a cell that relies on fatty acid oxidation (and some glycolysis), to one that engages robust aerobic glycolysis and glutaminolysis [2] (see Figure 1; here we focus on T lymphocytes, but similar events may well occur in activated B lymphocytes). This change relies on signaling events early in the activation process. For example, a hierarchical signaling cascade downstream of the cell surface receptors involved in MAPK (mitogen activated protein kinase)/ERK (extra-cellular signal-regulated kinase), PI3K (phosphoinositide 3-kinase)/Akt, mTOR (mammalian target of rapamycin) kinase and NFκB (nuclear factor-κB) pathways rapidly engages the expression of the transcription factor Myc, which, in turn, induces the expression of transporters for glucose and glutamine, and many of the enzymes involved in glycolysis, the pentose phosphate pathway, and glutaminolysis [2,3]. This reprogramming, thereby, directs nutrients to the production of nucleotides, lipids, amino acids, and other biosynthetic products needed for proliferation. Meanwhile, the activation of AKT and ERK facilitates post-translational surface expression of glucose transporter Glut-1 and glutamine transporter SNAT2 (system A neutral amino acid transporter 2), respectively [4,5]. However, AKT is dispensable for increased glycolysis and proliferation in cytotoxic CD8 T cells; although these effects depend on PDK1 (phosphoinositide-dependent protein kinase-1), a well-known upstream regulator of AKT [6]. TORC (TOR complex) 1, a downstream signaling component of Akt, also plays a role in maintaining the metabolic gene transcriptome in naïve quiescent T cells [7]. Meanwhile, the suppression of the nuclear receptor LXR (liver X receptor) enhances cholesterol synthesis, an essential component of membranes [8], and the activation of an orphan steroid receptor, ERRα (estrogen-related receptor α), promotes lipid production, and perhaps mitochondrial biogenesis [9]. Coordinately, these events most likely prepare the activated T cells for their entry into their rapid cell cycle.

Figure 1.
Metabolic reprogramming in T lymphocytes

T cell metabolism and differentiation

As T lymphocytes begin to proliferate they also undergo differentiation into functional subsets in response to extracellular signals, and these subsets determine the nature of the immune response. CD4 T cells differentiate into Th (T helper) 1 cells that mediate responses to intracellular pathogens, Th2 cells that control responses to extracellular bacteria and helminthes, Th17 cells that are important in anti-fungal defense and inflammation, and induced Treg (regulatory T) cells that dampen immune responses. Of these, only the Treg cells rely on lipid oxidation as an energy source, and forcing proliferating T cells to utilize free fatty acids for energy tends to drive enhanced Treg differentiation [10]. In contrast, increased glycolysis is seen in differentiating Th17 cells, and this is a function of the transcription factor HIF1 (hypoxia-inducible factor 1) [10,11]. Thus, damping of glycolysis with low dose 2-deoxyglucose inhibits Th17 and promotes Treg generation [11]. HIF1 also directly enhances RORγt activity and represses Foxp3 activity, producing a reciprocal increase in Th17 and decrease in iTreg differentiation [12]. Meanwhile, the choice between Th1, Th2 and Th17 differentiation is mediated in part by TORC1/2, the activation of which requires a surplus of intracellular amino acids pool; TORC1 promotes Th1 and Th17 differentiation, while TORC2 promotes Th2 differentiation [13]. In addition, the depletion of extracellular amino acids, either by amino acid catabolic enzymes such as IDO (indoleamine 2,3-dioxygenase), Arg I (arginase I) and asparaginase or by the small molecule halofuginone, results in the activation of the protein kinase GCN2 (general control nonrepressed 2) in T cells [14-17]. Consequently, Th17 differentiation is suppressed, whereas Treg development and T cell anergy are enhanced [14,18]. Each of these regulatory “nodes” (HIF1, TORC, GCN2) are responsive to metabolic status (e.g. oxygen availability, intracellular ATP and amino acid pool), highlighting the connections between metabolism and T cell signaling.

Following the peak of proliferation and differentiation, there is a contraction phase as cells undergo apoptosis dependent on the pro-apoptotic proteins BIM and PUMA [19]. Cells destined to be memory T cells, responsible for enhanced immunity upon rechallenge, persist by employing fatty acid oxidation, the activity of which is associated with increased mitochondrial respiratory capacity and is negatively regulated by TORC1 activity [20-22]. The inhibition of TORC1 may require the function of the TSC (tuberous sclerosis protein) 1/2 complex, as cells lacking TSC1 do not generate immune memory [7].

Summary and future directions

We suspect that these studies merely “scratch the surface” of metabolic control of lymphocyte function. And of course, the immune response is not restricted to lymphocytes — the metabolic functions in cells of the innate immune system, including macrophages, dendritic cells, and others, are topics of ongoing investigation as well. Further, while much current work is directed at understanding how signaling pathways regulate metabolic changes, there are intriguing observations in these and other systems that support the converse; that is, that changes in metabolic substrates and products directly affect signaling. For example, the intracellular ATP and amino acid pools directly impact the activities of AMPK (AMP-activated protein kinase), TORC1 and GCN2 [14, 23, 24]. Further, enzymes in the metabolic pathways can also function in signaling. For example, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) has been implicated in the control of gene expression [25], and the glycolytic enzyme pyruvate kinase M2 isoform (PKM2) (expressed in cancers [26] and activated lymphocytes [2]) engages β-catenin signaling independently of Wnt [27]. We may intuit that these, and other critical enzymes, are likely to link metabolic status to signaling.

A great deal of excitement has followed the metabolic control of cancer in pointing the way to new therapies. The same may well apply to metabolic control of dysregulated autoimmune disease. These studies hold the promise for a renaissance in nutritional research, far beyond the “immune diet” fads, based on fundamental principles of the emerging connections between signaling pathways and metabolism.


We thank the members of the Green laboratory for valuable discussions. This work was supported by the George J. Mitchell fellowship from St Jude Children Hospital (R.W.), NIH grants AI40646 and GM52735 (D.R.G.) and the American Lebanese and Syrian Associated Charities.


extra-cellular signal-regulated kinase
general control nonrepressed 2
hypoxia-inducible factor 1
T helper cell
TOR complex
regulatory T
tuberous sclerosis protein


The electronic version of this article is the complete one and can be found at:


Competing Interests

The authors declare that they have no competing financial interests.


1. van Stipdonk MJ, Hardenberg G, Bijker MS, Lemmens EE, Droin NM, Green DR, Schoenberger SP. Dynamic programming of CD8+ T lymphocyte responses. Nat Immunol. 2003;4:361–65. doi: 10.1038/ni912. [PubMed] [Cross Ref]
2. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR. The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation. Immunity. 2011;35:871–82. doi: 10.1016/j.immuni.2011.09.021. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 10
Evaluated by Laurence Morel 23 Jan 2012, David Fruman 31 Jan 2012, Ivan Gerling and Dorothy Kakoola 17 Feb 2012
3. Grumont R, Lock P, Mollinari M, Shannon FM, Moore A, Gerondakis S. The mitogen-induced increase in T cell size involves PKC and NFAT activation of Rel/NF-kappaB-dependent c-myc expression. Immunity. 2004;21:19–30. doi: 10.1016/j.immuni.2004.06.004. [PubMed] [Cross Ref] F1000 Factor 6
Evaluated by Douglas Green 16 Apr 2012
4. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–77. doi: 10.1016/S1074-7613(02)00323-0. [PubMed] [Cross Ref] F1000 Factor 7
Evaluated by Steve Ward 23 Jul 2002, Douglas Green 16 Apr 2012
5. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol. 2011;185:1037–44. doi: 10.4049/jimmunol.0903586. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 9
Evaluated by Peter Taylor 25 Aug 2010, Douglas Green 16 Apr 2012
6. Macintyre AN, Finlay D, Preston G, Sinclair LV, Waugh CM, Tamas P, Feijoo C, Okkenhaug K, Cantrell DA. Protein Kinase B Controls Transcriptional Programs that Direct Cytotoxic T Cell Fate but Is Dispensable for T Cell Metabolism. Immunity. 2011;34:224–36. doi: 10.1016/j.immuni.2011.01.012. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 10
Evaluated by Amnon Altman 07 Mar 2011, David Fruman 14 Mar 2011, Douglas Green 16 Apr 2012
7. Yang K, Neale G, Green DR, He W, Chi H. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol. 2011;12:888–97. doi: 10.1038/ni.2068. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 8
Evaluetd by Philippe Bousso and Jacques Deguine 17 Oct 2011
8. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008;134:97–111. doi: 10.1016/j.cell.2008.04.052. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 12
Evaluated by Percy Knolle 15 Oct 2008, David Mangelsdorf and Klementina Fon Tacer 27 Oct 2008, Douglas Green 16 Apr 2012
9. Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY, Dwyer MA, Nelson ER, Pollizzi KN, Ilkayeva O, Giguere V, Zuercher WJ, Powell JD, Shinohara ML, McDonnell DP, Rathmell JC. Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U S A. 2011;108:18348–53. doi: 10.1073/pnas.1108856108. [PubMed] [Cross Ref] F1000 Factor 12
Evalauted by David Fruman 09 Jan 2012, Ivan Gerling and Dorothy Kakoola 11 Jan 2012, Douglas Green 16 Apr 2012
10. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186:3299–303. doi: 10.4049/jimmunol.1003613. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 9
Evaluated by Andrew Weinberg 23 May 2011, Douglas Green 16 Apr 2012
11. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208:1367–76. doi: 10.1084/jem.20110278. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 10
Evalauted by Richard Williams 01 Jul 2011, Muriel Moser and Oberdan Leo 08 Jul 2011, Klaus Rajewsky and Sergei Koralov 27 Oct 2011
12. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146:772–84. doi: 10.1016/j.cell.2011.07.033. [PubMed] [Cross Ref] F1000 Factor 16
Evaluated by Ronald Germain and Wolfgang Kastenmuller 22 Sep 2011, Barry Rouse 30 Sep 2011, Philippe Bousso and Jacques Deguine 25 Oct 2011, Douglas Green 16 Apr 2012
13. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12:295–303. doi: 10.1038/ni.2005. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 8
Evalauted by Toshinori Nakayama and Damon Tumes 19 Apr 2011, Susan Kaech and Weiguo Cui 10 May 2011, Douglas Green 16 Apr 2012
14. Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M, Keller T, Rao A. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science. 2009;324:1334–8. doi: 10.1126/science.1172638. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 6
Evaluated by Douglas Green 16 Apr 2012
15. Huang L, Baban B, Johnson BA, 3rd, Mellor AL. Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int Rev Immunol. 2010;29:133–55. doi: 10.3109/08830180903349669. [PubMed] [Cross Ref] F1000 Factor 6
Evaluated by Douglas Green 16 Apr 2012
16. Bunpo P, Cundiff JK, Reinert RB, Wek RC, Aldrich CJ, Anthony TG. The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase. J Nutr. 2010;140:2020–7. doi: 10.3945/jn.110.129197. [PubMed] [Cross Ref] F1000 Factor 6
Evaluated by Douglas Green 16 Apr 2012
17. Nicholson LB, Raveney BJ, Munder M. Monocyte dependent regulation of autoimmune inflammation. Curr Mol Med. 2009;9:23–9. doi: 10.2174/156652409787314499. [PubMed] [Cross Ref]
18. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633–42. doi: 10.1016/j.immuni.2005.03.013. [PubMed] [Cross Ref] F1000 Factor 9
Evaluated by Richard Williams 01 Jul 2005, Douglas Green 16 Apr 2012
19. Green DR. Fas Bim boom! Immunity. 2008;28:141–3. doi: 10.1016/j.immuni.2008.01.004. [PubMed] [Cross Ref]
20. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009;460:103–7. doi: 10.1038/nature08097. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 14
Evaluated by Allan Zajac 09 Jun 2009, Susan Kaech 17 Jun 2009, John Kyriakis 03 Jul 2009, Anthony Means 14 Jul 2009, Mark Boothby 07 Aug 2009
21. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460:108–12. doi: 10.1038/nature08155. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 24
Evaluated by Barry Rouse 22 Jun 2009, Marcia Blackman 26 Jun 2009, Torben Lund 06 Jul 2009, Allan Zajac 14 Jul 2009, Paul Klenerman 16 Jul 2009, Ronald Germain and Wolfgang Kastenmuller 22 Sep 2009, Jay Berzofsky 14 Oct 2009, Douglas Green 16 Apr 2012
22. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL. Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8(+) T Cell Memory Development. Immunity. 2012;36:68–78. doi: 10.1016/j.immuni.2011.12.007. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 11
Evaluated by Tania Watts 16 Jan 2012, Howard Petrie 15 Mar 2012, Douglas Green 16 Apr 2012
23. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13:1016–23. doi: 10.1038/ncb2329. [PMC free article] [PubMed] [Cross Ref]
24. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12:21–35. doi: 10.1038/nrm3025. [PubMed] [Cross Ref]
25. Zheng L, Roeder RG, Luo Y. S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell. 2003;114:255–66. doi: 10.1016/S0092-8674(03)00552-X. [PubMed] [Cross Ref] F1000 Factor 22
Evalauted by Ronald Conaway 13 Aug 2003, Dinah Singer 14 Aug 2003, Ueli Schibler 14 Aug 2003, Stephen Dalton 20 Aug 2003, Patrick Matthias 16 Oct 2003, Michael Meisterernst 04 Nov 2003, Andrew D Sharrocks 26 Nov 2003, Douglas Green 16 Apr 2012
26. Mazurek S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol. 2011;43:969–80. doi: 10.1016/j.biocel.2010.02.005. [PubMed] [Cross Ref] F1000 Factor 6
Evaluated by Douglas Green 16 Apr 2012
27. Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, Gao X, Aldape K, Lu Z. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature. 2011;480:118–22. doi: 10.1038/nature10598. [PMC free article] [PubMed] [Cross Ref] F1000 Factor 6
Evaluated by Douglas Green 16 Apr 2012

Articles from F1000 Biology Reports are provided here courtesy of Faculty of 1000 Ltd