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Futility Sustains Memory T Cells

2014; Cell Press; Volume: 41; Issue: 1 Linguagem: Inglês

10.1016/j.immuni.2014.06.009

1097-4180

Samuel E. Weinberg, Navdeep S. Chandel,

Cancer, Hypoxia, and Metabolism

Memory T cells display a distinct metabolic profile compared to effector T cells. In this issue of Immunity, O’Sullivan et al., 2014O’Sullivan D. van der Windt G.J.W. Huang S.C.-C. Curtis J.D. Chang C.-H. Buck M.D. Qiu J. Smith A.M. Lam W.Y. DiPlato L.M. et al.Immunity. 2014; 41 (this issue): 75-88Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar report that memory T cells activate a “futile cycle” of de novo fatty-acid synthesis and concurrent fatty-acid oxidation to generate ATP for cell survival. Memory T cells display a distinct metabolic profile compared to effector T cells. In this issue of Immunity, O’Sullivan et al., 2014O’Sullivan D. van der Windt G.J.W. Huang S.C.-C. Curtis J.D. Chang C.-H. Buck M.D. Qiu J. Smith A.M. Lam W.Y. DiPlato L.M. et al.Immunity. 2014; 41 (this issue): 75-88Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar report that memory T cells activate a “futile cycle” of de novo fatty-acid synthesis and concurrent fatty-acid oxidation to generate ATP for cell survival. T cells are primary cells that respond to antigens and thus are central regulators of adaptive immune responses. Aberrant T cell function results in a multitude of pathologies including autoimmunity. There are multiple different types of T cells with different metabolic requirements. Naive T cells (Tn) rapidly proliferate into effector T cells (Teff) when challenged with an antigen during infection. After the infection is curtailed, the majority of Teff cells undergo cell death (i.e., contraction phase) with a few surviving long-lived memory T cells (Pearce et al., 2013Pearce E.L. Poffenberger M.C. Chang C.H. Jones R.G. Science. 2013; 342: 1242454Crossref PubMed Scopus (823) Google Scholar). If a similar infection occurs, then memory T cells can be reactivated, rapidly expanding into Teff cells to quickly control the infection. Tn cells are quiescent cells that catabolize nutrients to generate ATP for cell survival and engage in anabolic functions to maintain homeostasis (MacIver et al., 2013MacIver N.J. Michalek R.D. Rathmell J.C. Annu. Rev. Immunol. 2013; 31: 259-283Crossref PubMed Scopus (818) Google Scholar). By contrast, rapidly proliferating Teff cells uptake nutrients such as glucose to produce ATP and NADPH, as well as de novo lipids and nucleotides—macromolecules necessary to generate two daughter cells (MacIver et al., 2013MacIver N.J. Michalek R.D. Rathmell J.C. Annu. Rev. Immunol. 2013; 31: 259-283Crossref PubMed Scopus (818) Google Scholar). Anabolic functions require ATP and NADPH. Teff cells increase the rate of glycolysis and mitochondrial metabolism to sustain the high anabolic needs of proliferating Teff cells. Glucose and glutamine serve as primary carbon sources to fuel glycolysis and mitochondrial metabolism to generate metabolites that are precursors for macromolecule biosynthesis (Michalek et al., 2011Michalek R.D. Gerriets V.A. Jacobs S.R. Macintyre A.N. MacIver N.J. Mason E.F. Sullivan S.A. Nichols A.G. Rathmell J.C. J. Immunol. 2011; 186: 3299-3303Crossref PubMed Scopus (1310) Google Scholar, Wang et al., 2011Wang R. Dillon C.P. Shi L.Z. Milasta S. Carter R. Finkelstein D. McCormick L.L. Fitzgerald P. Chi H. Munger J. Green D.R. Immunity. 2011; 35: 871-882Abstract Full Text Full Text PDF PubMed Scopus (1315) Google Scholar). Aside from metabolism simply responding to the anabolic demands of proliferating cells, metabolism also dictates signaling. Notably, the glycolytic enzyme GAPDH and mitochondrial generated reactive oxygen species control effector T cell cytokine production (Chang et al., 2013Chang C.H. Curtis J.D. Maggi Jr., L.B. Faubert B. Villarino A.V. O’Sullivan D. Huang S.C. van der Windt G.J. Blagih J. Qiu J. et al.Cell. 2013; 153: 1239-1251Abstract Full Text Full Text PDF PubMed Scopus (1323) Google Scholar, Sena et al., 2013Sena L.A. Li S. Jairaman A. Prakriya M. Ezponda T. Hildeman D.A. Wang C.R. Schumacker P.T. Licht J.D. Perlman H. et al.Immunity. 2013; 38: 225-236Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar). By contrast, memory T cells are not rapidly proliferating and thus do not have high anabolic requirements. However, memory T cells need to efficiently catabolize nutrients to maintain long-term cell survival. A critical question is how these long-lived memory T cells maintain their bioenergetic needs to maintain cell survival. In this issue of Immunity, O’Sullivan et al., 2014O’Sullivan D. van der Windt G.J.W. Huang S.C.-C. Curtis J.D. Chang C.-H. Buck M.D. Qiu J. Smith A.M. Lam W.Y. DiPlato L.M. et al.Immunity. 2014; 41 (this issue): 75-88Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar investigated the metabolic pathways that support survival of memory T cells. Previously, their laboratory had shown that memory T cells display high levels of fatty-acid oxidation by mitochondria to produce ATP compared to Teff cells for long-term cell survival (van der Windt et al., 2012van der Windt G.J. Everts B. Chang C.H. Curtis J.D. Freitas T.C. Amiel E. Pearce E.J. Pearce E.L. Immunity. 2012; 36: 68-78Abstract Full Text Full Text PDF PubMed Scopus (945) Google Scholar). Fatty-acid oxidation generates almost three times more ATP than glucose oxidation by mitochondria, and thus it is a robust mechanism to generate ATP. But where do memory T cells acquire fatty acids to conduct fatty-acid oxidation? Their original assumption was that memory T cells simply uptake fatty acids from their environment. Conceptually this makes sense since memory T cells reside in adipose rich tissues. Thus, they were surprised that compared with Teff cells, memory T cells obtained significantly less fatty acids from the environment. Memory T cells displayed a decrease in the surface expression of CD36, necessary for fatty-acid uptake, compared with Teff cells, thus providing a potential mechanism for differences in the rate of fatty-acid uptake between memory T cells and Teff cells. Fatty acids acquired by Teff cells are stored in lipid droplets and therefore are not used to generate ATP by mitochondrial fatty-acid oxidation. By contrast, memory T cells do not increase fatty-acid uptake even in a setting of increased fatty-acid oxidation. Consequently, O’Sullivan et al. questioned what the source of fatty acids is to drive the heightened levels of fatty-acid oxidation in memory T cells, since memory T cells do not acquire fatty acids from the environment to increase the rate of fatty-acid oxidation. The authors reasoned that because memory T cells display no increase in extracellular fatty-acid uptake, then de novo fatty-acid synthesis might provide the necessary fatty acids to generate mitochondrial ATP through fatty-acid oxidation. To test this hypothesis, O’Sullivan et al. utilized C75, an inhibitor of the fatty-acid synthase—an enzyme necessary for fatty-acid synthesis—and observed that C75 increased memory T cell death. C75 did not impair Teff cell survival but diminished Teff cell proliferation. These results indicate that de novo fatty-acid synthesis is essential for memory T cell survival and Teff cell proliferation (Figure 1). Next, the authors probed whether glucose-derived citrate was one of the major cellular carbon sources for de novo fatty-acid synthesis in both memory T and Teff cells. Glucose generates pyruvate that becomes acetyl-CoA to enter the TCA cycle. TCA cycle intermediates acetyl-CoA and oxaloacetate generate citrate, which can be exported into the cytosol for de novo lipogenesis (Menendez and Lupu, 2007Menendez J.A. Lupu R. Nat. Rev. Cancer. 2007; 7: 763-777Crossref PubMed Scopus (2020) Google Scholar). The cytosolic enzyme ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate. The former is a precursor for lipogenesis, whereas the latter is utilized for de novo nucleotide synthesis. Unexpectedly silencing ACLY protein by RNAi did not impair cell survival of memory T cells but did decrease Teff cell proliferation. Hence, it is possible that memory T cells generate cytosolic acetyl-CoA through other metabolites than citrate. Notably, acetate can be converted into to acetyl-CoA by the enzyme acetyl-CoA synthetase. Gut bacteria can generate acetate, thus possibly linking the microbiome to memory T cells. At this point, the authors recognized that some of their findings displayed an inherent contradiction. Classically, free fatty acids produced by a cell are quickly diverted into triglyceride storage in adipocyte-like droplets to prevent toxic effects of high levels of free fatty acids. However, in the case of memory T cells, O’Sullivan and colleagues had observed no appreciable accumulation of lipid droplets. The authors then reasoned that a nonclassical pathway of fatty-acid storage was being used and identified increased activity of lysosomal acid lipase (LAL) in memory T cells along with elevated lipid levels localizing to the lysosome. These data strongly suggested that memory T cells in contrast to Teff cells activate a lysosomal-based lipid storage and degradation pathway. Next, using small hairpin RNA silencing of LAL in fully activated T cells, the authors showed that memory T cells required LAL to liberate free fatty acids from storage for the robust fatty-acid oxidation in the mitochondria. Finally, the authors demonstrated that loss of LAL activity during an immune response greatly reduced the amount of memory T cells produced, which was due to a decrease in survival of memory T cells. Collectively, these data support the idea that activation of the “futile cycle” where fatty-acid synthesis with concurrent fatty-acid oxidation is required for proper maintenance of memory T cells (Figure 1). From a bioenergetic perspective, this is an inefficient use of macronutrients because these cells must first use ATP and NADPH to synthesize the fatty acids that ultimately will be used to generate ATP. There are biochemical mechanisms to prevent the futile cycle from arising. An early step in fatty-acid synthesis is the generation of malonyl-CoA, which prevents fatty acid import into the mitochondria as it increases in concentration (Foster, 2012Foster D.W. J. Clin. Invest. 2012; 122: 1958-1959Crossref PubMed Scopus (206) Google Scholar). Although O’Sullivan et al. did not decipher the biochemical basis as to how memory T cells evade this regulatory cell, the possibility is raised that long-lived cells might utilize the futile cycle to maintain their survival. It will be of interest to examine whether certain long-lived stem cells, cancer initiating cells, or senescent cells utilize the futile cycle to maintain long-term cell survival. It is important to note that it is formally possible that memory T cells within a population do not necessarily engage in a futile cycle but oscillate between fatty-acid synthesis and fatty-acid oxidation. Going forward, it will be meaningful to decipher what the metabolic advantage is of engaging the futile cycle for memory T cells. Here we speculate two possibilities. First, memory T cells might employ the futile cycle to concurrently maintain robust mitochondrial oxidative metabolism and glycolysis. This has the potential advantage of allowing memory T cells the capacity to rapidly use glycolytic and mitochondrial metabolism following a re-encounter with antigen for rapid proliferation and cytokine production. Second, memory T cells might decide that reliance on extracellular fatty acids could be risky because fatty-acid levels vacillate depending on the tissues where they reside. Thus, memory cells decide to take up glucose, an abundant nutrient in the blood that is tightly regulated to maintain levels between 5 and 6 mM, in order to generate de novo fatty acids for mitochondrial ATP production needed to maintain long term cell survival. Hence, O’Sullivan et al. have not only uncovered an interesting observation for the burgeoning field of immunometabolism but also raised stimulating questions for biochemists to think about regulation of metabolic pathways. Specifically, biochemists will have to incorporate futile metabolic pathways in trying to understand how nutrients fulfill the metabolic demands of cells. Memory CD8+ T Cells Use Cell-Intrinsic Lipolysis to Support the Metabolic Programming Necessary for DevelopmentO’Sullivan et al.ImmunityJuly 4, 2014In BriefCD8+ memory T cells engage fatty-acid oxidation (FAO); however, the source of fatty acids that fuel FAO is unclear. O’Sullivan et al. show that memory T cells rely on glucose, and cell-intrinsic lipolysis to mobilize substrates, for FAO. Full-Text PDF Open Archive