Enhancing CD8 T-cell memory by modulating fatty acid metabolism
Open accessAbstract
CD8 T cells, which have a crucial role in immunity to infection and cancer, are maintained in constant numbers, but on antigen stimulation undergo a developmental program characterized by distinct phases encompassing the expansion and then contraction of antigen-specific effector (T(E)) populations, followed by the persistence of long-lived memory (T(M)) cells. Although this predictable pattern of CD8 T-cell responses is well established, the underlying cellular mechanisms regulating the transition to T(M) cells remain undefined. Here we show that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates CD8 T(M)-cell development after infection by modulating fatty acid metabolism. We show that mice with a T-cell-specific deletion of TRAF6 mount robust CD8 T(E)-cell responses, but have a profound defect in their ability to generate T(M) cells that is characterized by the disappearance of antigen-specific cells in the weeks after primary immunization. Microarray analyses revealed that TRAF6-deficient CD8 T cells exhibit altered expression of genes that regulate fatty acid metabolism. Consistent with this, activated CD8 T cells lacking TRAF6 display defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and CD8 T(M)-cell generation in the absence of TRAF6. This treatment also increased CD8 T(M) cells in wild-type mice, and consequently was able to considerably improve the efficacy of an experimental anti-cancer vaccine.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Metformin enhances T cell memory generation in mice when administered after primary immunization.
“metformin was shown to enhance T cell memory generation in mice when administered after primary immunization [75].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [75]
Memory CD8+ T cells (Tm) contain more mitochondria and have greater spare respiratory capacity, supported by fatty acid oxidation for ATP production.
“Tm cells display increased mitochondrial number and spare respiratory capacity, which is fueled by fatty acid oxidation to generate copious amount of ATP (Pearce et al., 2009; van der Windt et al., 2012).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as Pearce et al., 2009
Reducing or increasing AMPK, a positive regulator of fatty acid oxidation, respectively decreases or increases memory T cell formation.
“The importance of fatty acid oxidation for Tm cells is bolstered by the observations that diminishing or enhancing AMPK, a positive regulator of fatty acid oxidation, decreases or increases formation of memory T cells (MacIver et al., 2011; Pearce et al., 2009; Rolf et al., 2013; Tamás et al., 2010).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as Pearce et al., 2009
FAO is fundamental for the survival and function of memory CD8+ T cells, unlike effector cells that rely on glycolysis and glutaminolysis for energy.
“FAO is fundamental for the survival and function of memory CD8+ T cells, unlike effector cells that rely on glycolysis and glutaminolysis for energy.60,61”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [60]
Rapamycin, which inhibits mTORC1, enhances generation of CD8 memory T cells.
“Consistent with this, the drug rapamycin, which also inhibits mTORC1, enhances the generation of CD8 TM cells (17, 19, 20).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [17]
Mitochondrial FAO stimulated downstream of TRAF6 is required for memory CD8+ T cell development.
“We previously demonstrated that mitochondrial FAO stimulated downstream of TNF (tumor necrosis factor) receptor–associated factor 6 (TRAF6) is required for memory CD8+ T cell development (17).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [17]
Administration of metformin enhances generation of CD8+ T cell memory.
“Administration of metformin, a metabolic stressor that activates the energy sensor adenosine monophosphate–activated protein kinase (AMPK), enhances the generation of CD8+ T cell memory (17).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [17]
The AMPK agonist metformin, which promotes FAO in activated T cells, enhances the production of CD8+ memory T cells in vivo.
“As evidence for this, the AMPK agonist metformin, which promotes FAO in activated T cells, enhances the production of CD8+ memory T cells in vivo (17).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [17]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Bioconductor: open software development for computational biology and bioinformatics
Gentleman, R., Carey, V., Bates, D., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004) · Genome Biology · doi:10.1186/gb-2004-5-10-r80 · Cited by 13,133 · see citing works
limma: Linear Models for Microarray Data
Smyth, G. K. (2005) · Statistics for Biology and Health · doi:10.1007/0-387-29362-0_23 · Cited by 5,796 · see citing works
Bioinformatics and Computational Biology Solutions Using R and Bioconductor
Gentleman, R. C., Carey, V. J., Huber, W. K., Irizarry, R. A., & Dudoit, S. (2005) · Statistics in the health sciences · doi:10.1007/0-387-29362-0 · Cited by 3,470 · see citing works
Joshi, N. S., Cui, W., Chandele, A., Lee, H. K., Urso, D. R., Hagman, J., Gapin, L., & Kaech, S. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.010 · Cited by 1,861 · see citing works
Kaech, S. M., Tan, J. T., Wherry, E. J., Konieczny, B. T., Surh, C. D., & Ahmed, R. (2003) · Nature Immunology · doi:10.1038/ni1009 · Cited by 1,830 · see citing works
A Model-Based Background Adjustment for Oligonucleotide Expression Arrays
Wu, Z. J., Irizarry, R. A., Gentleman, R. C., Martínez-Murillo, F., & Spencer, F. A. (2004) · Journal of the American Statistical Association · doi:10.1198/016214504000000683 · Cited by 1,717 · see citing works
CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes
Janssen, E. M., Lemmens, E. E., Wolfe, T., Christen, U., von Herrath, M. G., & Schoenberger, S. P. (2003) · Nature · doi:10.1038/nature01441 · Cited by 1,635 · see citing works
Interleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo
Schluns, K. S., Kieper, W. C., Jameson, S. C., & Lefrançois, L. (2000) · Nature Immunology · doi:10.1038/80868 · Cited by 1,619 · see citing works
Growth factor regulation of autophagy and cell survival in the absence of apoptosis
Lum, J. J., Bauer, D. E., Kong, M., Harris, M. H., Li, C., Lindsten, T., & Thompson, C. B. (2005) · Cell · doi:10.1016/j.cell.2004.11.046 · Cited by 1,487 · see citing works
The CD28 Signaling Pathway Regulates Glucose Metabolism
Frauwirth, K. A., Riley, J. L., Harris, M. H., Parry, R. V., Rathmell, J. C., Plas, D. R., Elstrom, R. L., June, C. H., & Thompson, C. B. (2002) · Immunity · doi:10.1016/s1074-7613(02)00323-0 · Cited by 1,475 · see citing works
Akt Stimulates Aerobic Glycolysis in Cancer Cells
Elstrom, R. L., Bauer, D. E., Buzzai, M., Karnauskas, R., Harris, M. H., Plas, D. R., Zhuang, H., Cinalli, R. M., Alavi, A., Rudin, C. M., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-2904 · Cited by 1,454 · see citing works
Requirement for CD4 T Cell Help in Generating Functional CD8 T Cell Memory
Shedlock, D. J., & Shen, H. (2003) · Science · doi:10.1126/science.1082305 · Cited by 1,450 · see citing works
Self-citationDefective CD8 T Cell Memory Following Acute Infection Without CD4 T Cell Help
Sun, J. C., & Bevan, M. J. (2003) · Science · doi:10.1126/science.1083317 · Cited by 1,213 · see citing works
Introduction of soluble protein into the class I pathway of antigen processing and presentation
Moore, M. W., Carbone, F. R., & Bevan, M. J. (1988) · Cell · doi:10.1016/s0092-8674(88)91043-4 · Cited by 1,092 · see citing works
Buzzai, M., Jones, R. G., Amaravadi, R. K., Lum, J. J., DeBerardinis, R. J., Zhao, F., Viollet, B., & Thompson, C. B. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4447 · Cited by 923 · see citing works
Self-citationFuel feeds function: energy metabolism and the T-cell response
Fox, C. J., Hammerman, P. S., & Thompson, C. B. (2005) · Nature reviews. Immunology · doi:10.1038/nri1710 · Cited by 841 · see citing works
Tan, J. T., Ernst, B., Kieper, W. C., LeRoy, E., Sprent, J., & Surh, C. D. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020066 · Cited by 790 · see citing works
Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b
Bachmaier, K., Krawczyk, C. M., Kozieradzki, I., Kong, Y., Sasaki, T., Oliveira-dos-Santos, A., Mariathasan, S., Bouchard, D., Wakeham, A. C., Itié, A., et al. (2000) · Nature · doi:10.1038/35003228 · Cited by 674 · see citing works
Shaping and reshaping CD8+ T-cell memory
Harty, J. T., & Badovinac, V. P. (2008) · Nature reviews. Immunology · doi:10.1038/nri2251 · Cited by 548 · see citing works
Schluns, K. S., Williams, K., Ma, A. I., Zheng, X. X., & Lefrançois, L. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.10.4827 · Cited by 521 · see citing works
Progressive differentiation and selection of the fittest in the immune response
Lanzavecchia, A., & Sallusto, F. (2002) · Nature Reviews Immunology · doi:10.1038/nri959 · Cited by 495 · see citing works
Rathmell, J. C., Heiden, M. G. V., Harris, M. H., Frauwirth, K. A., & Thompson, C. B. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00066-6 · Cited by 467 · see citing works
Badovinac, V. P., Haring, J. S., & Harty, J. T. (2007) · Immunity · doi:10.1016/j.immuni.2007.04.013 · Cited by 406 · see citing works
Peng, T., Golub, T. R., & Sabatini, D. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5575-5584.2002 · Cited by 397 · see citing works
Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice
Huang, X., Wullschleger, S., Shpiro, N., McGuire, V. A., Sakamoto, K., Woods, Y. L., Mcburnie, W., Fleming, S., & Alessi, D. R. (2008) · Biochemical Journal · doi:10.1042/bj20080557 · Cited by 396 · see citing works
Cutting Edge: CD4 and CD8 T Cells Are Intrinsically Different in Their Proliferative Responses
Foulds, K. E., Zenewicz, L. A., Shedlock, D. J., Jiang, J. K., Troy, A. E., & Shen, H. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.4.1528 · Cited by 385 · see citing works
Self-citationBuzzai, M., Bauer, D. E., Jones, R. G., DeBerardinis, R. J., Hatzivassiliou, G., Elstrom, R. L., & Thompson, C. B. (2005) · Oncogene · doi:10.1038/sj.onc.1208622 · Cited by 357 · see citing works
Self-citationRevving the Engine: Signal Transduction Fuels T Cell Activation
Jones, R. G., & Thompson, C. B. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.008 · Cited by 349 · see citing works
Self-citationSurh, C. D., Boyman, O., Purton, J. F., & Sprent, J. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00401.x · Cited by 277 · see citing works
TRAF6 Is a Critical Factor for Dendritic Cell Maturation and Development
Kobayashi, T., Walsh, P. T., Walsh, M. C., Speirs, K. M., Chiffoleau, E., King, C. G., Hancock, W. W., Caamaño, J., Hunter, C. A., Scott, P., et al. (2003) · Immunity · doi:10.1016/s1074-7613(03)00230-9 · Cited by 267 · see citing works
Self-citationGeneration of CD8 T Cell Memory Is Regulated by IL-12
Pearce, E. L., & Shen, H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.4.2074 · Cited by 228 · see citing works
Self-citationDeBerardinis, R. J., Lum, J. J., & Thompson, C. B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608372200 · Cited by 221 · see citing works
Burchill, M. A., Goetz, C. A., Prlic, M., O’Neil, J. J., Harmon, I., Bensinger, S. J., Turka, L. A., Brennan, P., Jameson, S. C., & Farrar, M. A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.11.5853 · Cited by 211 · see citing works
TRAF6 is a T cell–intrinsic negative regulator required for the maintenance of immune homeostasis
King, C. G., Kobayashi, T., Cejas, P. J., Kim, T. S., Yoon, K., Kim, G. K., Chiffoleau, E., Hickman, S. P., Walsh, P. T., Turka, L. A., et al. (2006) · Nature Medicine · doi:10.1038/nm1449 · Cited by 206 · see citing works
Self-citationThe mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes
Brown, N. F., Stefanović-Račić, M., SIPULA, I. J., & Perdomo, G. (2007) · Metabolism · doi:10.1016/j.metabol.2007.06.016 · Cited by 152 · see citing works
Requirements for CD8 T-cell priming, memory generation and maintenance
Prlic, M., Williams, M. A., & Bevan, M. J. (2007) · Current Opinion in Immunology · doi:10.1016/j.coi.2007.04.010 · Cited by 131 · see citing works
SIPULA, I. J., Brown, N. F., & Perdomo, G. (2006) · Metabolism · doi:10.1016/j.metabol.2006.08.002 · Cited by 118 · see citing works
Jones, R. G., Bui, T., White, C., Madesh, M., Krawczyk, C. M., Lindsten, T., Hawkins, B. J., Kubek, S., Frauwirth, K. A., Wang, Y. L., et al. (2007) · Immunity · doi:10.1016/j.immuni.2007.05.023 · Cited by 109 · see citing works
Self-citationA Role for Stat5 in CD8+ T Cell Homeostasis
Kelly, J., Spolski, R. J., Imada, K., Bollenbacher, J., Lee, S., & Leonard, W. J. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.1.210 · Cited by 80 · see citing works
Karst, A. M., Dai, D. L., Cheng, J. Q., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3633 · Cited by 43 · see citing works
Prevention of lethal acute GVHD with an agonistic CD28 antibody and rapamycin
Albert, M. H., Yu, X., Martin, P. J., & Anasetti, C. (2005) · Blood · doi:10.1182/blood-2004-08-3305 · Cited by 28 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [35]Buzzai M Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth Cancer Res 2007 67 14 6745 17638885
Cited by
Sorted by citations
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204 · see citing works
Self-citationThe transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D., McCormick, L. L., Fitzgerald, P., Chi, H., Munger, J., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.021 · Cited by 2,140 · see citing works
“, 2008), and the mammalian target of rapamycin (mTOR), an essential component of PI3K-Akt pathway, has recently been implicated in regulating fatty acid metabolism in memory T cells (Pearce et al., 2009; Araki et al., 2009).”
BackgroundDefining CD8+ T cells that provide the proliferative burst after PD-1 therapy
Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., et al. (2016) · Nature · doi:10.1038/nature19330 · Cited by 2,070 · see citing works
Michalek, 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. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003613 · Cited by 2,091 · see citing works
A human memory T cell subset with stem cell–like properties
Gattinoni, L., Lugli, E., Ji, Y., Pos, Z., Paulos, C. M., Quigley, M. F., Almeida, J. R., Gostick, E., Yu, Z., Carpenito, C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2446 · Cited by 1,974 · see citing works
The multifaceted contributions of mitochondria to cellular metabolism
Spinelli, J. B., & Haigis, M. C. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0124-1 · Cited by 1,935 · see citing works
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity
Geiger, R., Rieckmann, J. C., Wolf, T., Basso, C., Feng, Y., Fuhrer, T., Kogadeeva, M., Picotti, P., Meissner, F., Mann, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.09.031 · Cited by 1,775 · see citing works
Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20110278 · Cited by 1,803 · see citing works
Metabolic Pathways in Immune Cell Activation and Quiescence
Pearce, E. L., & Pearce, E. J. (2013) · Immunity · doi:10.1016/j.immuni.2013.04.005 · Cited by 1,692 · see citing works
Self-citationTranscriptional control of effector and memory CD8+ T cell differentiation
Kaech, S. M., & Cui, W. (2012) · Nature Reviews Immunology · doi:10.1038/nri3307 · Cited by 1,628 · see citing works
Metformin: from mechanisms of action to therapies
Foretz, M., Guigas, B., Bertrand, L., Pollak, M., & Viollet, B. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.09.018 · Cited by 1,501 · see citing works
Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development
van der Windt, G. J. W., Everts, B., Chang, C.-H., Curtis, J. D., Freitas, T. C., Amiel, E., Pearce, E. J., & Pearce, E. L. (2012) · Immunity · doi:10.1016/j.immuni.2011.12.007 · Cited by 1,540 · see citing works
Self-citationFueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
Self-citationHomeostatic Immunity and the Microbiota
Belkaid, Y., & Harrison, O. J. (2017) · Immunity · doi:10.1016/j.immuni.2017.04.008 · Cited by 1,261 · see citing works
Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Krawczyk, C. M., Holowka, T., Sun, J., Blagih, J., Amiel, E., DeBerardinis, R. J., Cross, J. R., Jung, E., Thompson, C. B., Jones, R. G., et al. (2010) · Blood · doi:10.1182/blood-2009-10-249540 · Cited by 1,246 · see citing works
Self-citationMetabolic Regulation of T Lymphocytes
MacIver, N. J., Michalek, R. D., & Rathmell, J. C. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095956 · Cited by 1,244 · see citing works
Metabolism of Inflammation Limited by AMPK and Pseudo-Starvation
O'Neill, L. A. J., & Hardie, D. G. (2013) · Nature · doi:10.1038/nature11862 · Cited by 1,133 · see citing works
Spermidine in health and disease
Madeo, F., Eisenberg, T., Pietrocola, F., & Kroemer, G. (2018) · Science · doi:10.1126/science.aan2788 · Cited by 1,154 · see citing works
Everts, B., Amiel, E., Huang, S. C.-C., Smith, A. M., Chang, C.-H., Lam, W. Y., Redmann, V., Freitas, T. C., Blagih, J., van der Windt, G. J. W., et al. (2014) · Nature Immunology · doi:10.1038/ni.2833 · Cited by 1,064 · see citing works
Self-citationRegulation and function of mTOR signalling in T cell fate decisions
Chi, H. (2012) · Nature Reviews Immunology · doi:10.1038/nri3198 · Cited by 1,035 · see citing works
Commensal bacteria at the interface of host metabolism and the immune system
Brestoff, J. R., & Artis, D. (2013) · Nature Immunology · doi:10.1038/ni.2640 · Cited by 945 · see citing works
Mitochondria in the Regulation of Innate and Adaptive Immunity
Weinberg, S. E., Sena, L. A., & Chandel, N. S. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.002 · Cited by 960 · see citing works
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Sukumar, M., Liu, J., Ji, Y., Subramanian, M., Crompton, J. G., Yu, Z., Roychoudhuri, R., Palmer, D. C., Muranski, P., Karoly, E. D., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69589 · Cited by 952 · see citing works
Sinclair, L. V., Rolf, J., Emslie, E., Shi, Y.-B., Taylor, P. M., & Cantrell, D. A. (2013) · Nature Immunology · doi:10.1038/ni.2556 · Cited by 930 · see citing works
Bengsch, B., Johnson, A. L., Kurachi, M., Odorizzi, P. M., Pauken, K. E., Attanasio, J., Stelekati, E., McLane, L. M., Paley, M. A., Delgoffe, G. M., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.07.008 · Cited by 868 · see citing works
“This treatmentmildly reduced the number of virus-specific T cells (Figures 4B and 4C) as expected based on the role of mTOR in effector CD8+ T cell expansion (Araki et al., 2009; Pearce et al., 2009).”
BackgroundAutophagy in inflammation, infection, and immunometabolism
Deretic, V. (2021) · Immunity · doi:10.1016/j.immuni.2021.01.018 · Cited by 862 · see citing works
Regulation of Immune Responses by mTOR
Powell, J. D., Pollizzi, K. N., Heikamp, E. B., & Horton, M. R. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075024 · Cited by 836 · see citing works
Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss
Lucas, S., Omata, Y., Hofmann, J., Böttcher, M., Iljazovic, A., Sarter, K., Albrecht, O., Schulz, O., Krishnacoumar, B., Krönke, G., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02490-4 · Cited by 815 · see citing works
O’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. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.005 · Cited by 790 · see citing works
Self-citationThe multifaceted role of CD4+ T cells in CD8+ T cell memory
Laidlaw, B. J., Craft, J. E., & Kaech, S. M. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2015.10 · Cited by 657 · see citing works
Rao, R. R., Li, Q., Odunsi, K., & Shrikant, P. A. (2010) · Immunity · doi:10.1016/j.immuni.2009.10.010 · Cited by 656 · see citing works
Alternative macrophage activation and metabolism
Odegaard, J. I., & Chawla, A. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130138 · Cited by 640 · see citing works
The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation
Bardhan, K., Anagnostou, T., & Boussiotis, V. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00550 · Cited by 606 · see citing works
T cells with dysfunctional mitochondria induce multimorbidity and premature senescence
Desdín-Micó, G., Soto-Heredero, G., Aranda, J. F., Oller, J., Carrasco, E., Gabandé-Rodríguez, E., Blanco, E. M., Alfranca, A., Cussó, L., Desco, M., et al. (2020) · Science · doi:10.1126/science.aax0860 · Cited by 572 · see citing works
Metformin: An Old But Still the Best Treatment for Type 2 Diabetes
Rojas, L. B. A., & Gomes, M. B. (2013) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-5-6 · Cited by 567 · see citing works
Metabolic switching and fuel choice during T‐cell differentiation and memory development
van der Windt, G. J. W., & Pearce, E. L. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01150.x · Cited by 563 · see citing works
Self-citationKidani, Y., Elsaesser, H., Hock, M. B., Vergnes, L., Williams, K. J., Argus, J. P., Marbois, B. N., Komisopoulou, E., Wilson, E. B., Osborne, T. F., et al. (2013) · Nature Immunology · doi:10.1038/ni.2570 · Cited by 552 · see citing works
Metformin as adjunct antituberculosis therapy
Singhal, A., Jie, L., Kumar, P., Hong, G. S., Leow, M. K.-S., Paleja, B., Tsenova, L., Kurepina, N., Chen, J., Zolezzi, F., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009885 · Cited by 547 · see citing works
Hirsch, H. A., Iliopoulos, D., & Struhl, K. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1221055110 · Cited by 440 · see citing works
The impact of obesity on the immune response to infection
Milner, J. J., & Beck, M. A. (2012) · Proceedings of The Nutrition Society · doi:10.1017/s0029665112000158 · Cited by 439 · see citing works
S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate
Tyrakis, P. A., Palazon, A., Macias, D., Lee, K. L., Phan, A. T., Veliça, P., You, J., Chia, G. S., Sim, J., Doedens, A., et al. (2016) · Nature · doi:10.1038/nature20165 · Cited by 433 · see citing works
<scp>mTOR</scp> , metabolism, and the regulation of T‐cell differentiation and function
Waickman, A. T., & Powell, J. D. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01152.x · Cited by 420 · see citing works
Chen, I. X., Chauhan, V. P., Posada, J., Ng, M. R., Wu, M. W., Adstamongkonkul, P., Huang, P., Lindeman, N., Langer, R., & Jain, R. K. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815515116 · Cited by 406 · see citing works
Rethinking inflammation: neural circuits in the regulation of immunity
Olofsson, P. S., Rosas‐Ballina, M., Levine, Y. A., & Tracey, K. J. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01138.x · Cited by 393 · see citing works
Autophagy in the renewal, differentiation and homeostasis of immune cells
Clarke, A. J., & Simon, A. K. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-018-0095-2 · Cited by 361 · see citing works
Autophagy is a critical regulator of memory CD8+ T cell formation
Puleston, D. J., Zhang, H., Powell, T. J., Lipina, E., Sims, S., Panse, I., Watson, A. S., Cerundolo, V., Townsend, A. R., Klenerman, P., et al. (2014) · eLife · doi:10.7554/elife.03706 · Cited by 360 · see citing works
Ray, J. P., Staron, M. M., Shyer, J. A., Ho, P.-C., Marshall, H. D., Gray, S. M., Laidlaw, B. J., Araki, K., Ahmed, R., Kaech, S. M., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.08.017 · Cited by 315 · see citing works
Metabolic regulation of inflammation
Gaber, T., Strehl, C., & Buttgereit, F. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.37 · Cited by 320 · see citing works
Metabolism in T cell activation and differentiation
Pearce, E. L. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.01.018 · Cited by 314 · see citing works
Self-citationGut bacteria signaling to mitochondria in intestinal inflammation and cancer
Jackson, D. N., & Theiss, A. L. (2020) · Gut Microbes · doi:10.1080/19490976.2019.1592421 · Cited by 312 · see citing works
Procaccini, C., Jirillo, E., & Matarese, G. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.10.012 · Cited by 299 · see citing works
Premature ovarian insufficiency: an international menopause society white paper
Panay, N., Anderson, R. A., Nappi, R. E., Vincent, A. J., Vujovic, S., Webber, L., & Wolfman, W. (2020) · Climacteric · doi:10.1080/13697137.2020.1804547 · Cited by 297 · see citing works
Repurposing metformin: an old drug with new tricks in its binding pockets
Pryor, R., & Cabreiro, F. (2015) · Biochemical Journal · doi:10.1042/bj20150497 · Cited by 280 · see citing works
Therapeutic cancer vaccines: Are we there yet?
Klebanoff, C. A., Acquavella, N., Yu, Z., & Restifo, N. P. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00979.x · Cited by 271 · see citing works
<scp>AMPK</scp> α1: A glucose sensor that controls <scp>CD</scp> 8 <scp>T</scp> ‐cell memory
Rolf, J., Zarrouk, M., Finlay, D. K., Foretz, M., Viollet, B., & Cantrell, D. A. (2013) · European Journal of Immunology · doi:10.1002/eji.201243008 · Cited by 245 · see citing works
Metformin and Other Biguanides in Oncology: Advancing the Research Agenda
Pollak, M. (2010) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-10-0175 · Cited by 240 · see citing works
The liver kinase B1 is a central regulator of T cell development, activation, and metabolism
MacIver, N. J., Blagih, J., Saucillo, D. C., Tonelli, L., Griss, T., Rathmell, J. C., & Jones, R. G. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100367 · Cited by 235 · see citing works
Self-citationSpermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice
Al-Habsi, M., Chamoto, K., Matsumoto, K., Nomura, N., Zhang, B., Sugiura, Y., Sonomura, K., Maharani, A., Nakajima, Y., Wu, Y., et al. (2022) · Science · doi:10.1126/science.abj3510 · Cited by 223 · see citing works
T cell Allorecognition Pathways in Solid Organ Transplantation
Siu, J. H. Y., Surendrakumar, V., Richards, J. A., & Pettigrew, G. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02548 · Cited by 223 · see citing works
Metabolic Barriers to T Cell Function in Tumors
Sugiura, A., & Rathmell, J. C. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701041 · Cited by 208 · see citing works
mTOR Regulation of Glycolytic Metabolism in T Cells
Salmond, R. J. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00122 · Cited by 211 · see citing works
Kabat, A. M., Harrison, O. J., Riffelmacher, T., Moghaddam, A. E., Pearson, C. F., Laing, A., Abeler-Dörner, L., Forman, S. P., Grencis, R. K., Sattentau, Q., et al. (2016) · eLife · doi:10.7554/elife.12444 · Cited by 193 · see citing works
Hu, J. K., Kagari, T., Clingan, J. M., & Matloubian, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1101881108 · Cited by 183 · see citing works
The metabolic life and times of a T‐cell
Michalek, R. D., & Rathmell, J. C. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00911.x · Cited by 186 · see citing works
“It is not certain precisely how TRAF6 may promote lipid b-oxidation, but the alternate approach to promote lipid oxidation by treatment of animals with the AMPK activator metformin was shown to enhance generation of memory T cells in a viral response model (117).”
BackgroundGatza, E., Wahl, D. R., Opipari, A. W., Sundberg, T. B., Reddy, P., Liu, C., Glick, G. D., & Ferrara, J. L. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3001975 · Cited by 168 · see citing works
New mechanisms of metformin action: Focusing on mitochondria and the gut
Hur, K. Y., & Lee, M. (2015) · Journal of Diabetes Investigation · doi:10.1111/jdi.12328 · Cited by 161 · see citing works
mTOR Signaling, Tregs and Immune Modulation
Chapman, N. M., & Chi, H. (2014) · Immunotherapy · doi:10.2217/imt.14.84 · Cited by 148 · see citing works
Alsaleh, G., Panse, I., Swadling, L., Zhang, H., Richter, F. C., Meyer, A., Lord, J., Barnes, E., Klenerman, P., Green, C., et al. (2020) · eLife · doi:10.7554/elife.57950 · Cited by 120 · see citing works
Selective inhibition of low-affinity memory CD8(+) T cells by corticosteroids
Tokunaga, A., Sugiyama, D., Maeda, Y., Warner, A. B., Panageas, K. S., Ito, S., Togashi, Y., Sakai, C., Wolchok, J. D., & Nishikawa, H. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20190738 · Cited by 124 · see citing works
The effects of metformin on gut microbiota and the immune system as research frontiers
Pollak, M. (2017) · Diabetologia · doi:10.1007/s00125-017-4352-x · Cited by 98 · see citing works
Vaena, S., Chakraborty, P., Lee, H. G., Janneh, A. H., Kassir, M. F., Beeson, G., Hedley, Z., Yalcinkaya, A., Sofi, M. H., Li, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109076 · Cited by 92 · see citing works
Powering the Immune System: Mitochondria in Immune Function and Deficiency
Walker, M. A., Volpi, S., Sims, K. B., Walter, J. E., & Traggiai, E. (2014) · Journal of Immunology Research · doi:10.1155/2014/164309 · Cited by 83 · see citing works
Paradoxical Aspects of Rapamycin Immunobiology in Transplantation
Ferrer, I. R., Araki, K., & Ford, M. L. (2011) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03473.x · Cited by 75 · see citing works
Metformin: prevention of genomic instability and cancer: a review
Najafi, M., Cheki, M., Rezapoor, S., Geraily, G., Motevaseli, E., Carnovale, C., Clementi, E., & Shirazi, A. (2018) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2018.01.007 · Cited by 75 · see citing works
The effects of age and systemic metabolism on anti-tumor T cell responses
Drijvers, J. M., Sharpe, A. H., & Haigis, M. C. (2020) · eLife · doi:10.7554/elife.62420 · Cited by 69 · see citing works
“Accordingly, memory T cell generation is promoted by metformin-induced AMPK activation as well as rapamycin-mediated mTOR inhibition (Araki et al., 2009; Pearce et al., 2009).”
BackgroundInfluentialImmune memory and aging: an infinite or finite resource?
Nikolich-Žugich, J., & Rudd, B. D. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.06.011 · Cited by 58 · see citing works
Energy metabolism and rheumatic diseases: from cell to organism
Spies, C. M., Straub, R. H., & Buttgereit, F. (2012) · Arthritis Research & Therapy · doi:10.1186/ar3885 · Cited by 47 · see citing works
Rapid linkage of innate immunological signals to adaptive immunity by the brain-fat axis
Kim, M. S., Yan, J., Wu, W., Zhang, G., Zhang, Y., & Cai, D. (2015) · Nature Immunology · doi:10.1038/ni.3133 · Cited by 40 · see citing works
An interferon gamma response signature links myocardial aging and immunosenescence
Ashour, D., Rebs, S., Arampatzi, P., Saliba, A.-E., Dudek, J., Schulz, R., Hofmann, U., Frantz, S., Cochain, C., Streckfuß-Bömeke, K., et al. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad068 · Cited by 39 · see citing works
Metformin and cancer: licence to heal?
Papanas, N., Maltezos, E., & Mikhailidis, D. P. (2010) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2010.499122 · Cited by 37 · see citing works
TCR-signaling events in cellular metabolism and specialization
Chisolm, D. A., & Weinmann, A. S. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00292 · Cited by 26 · see citing works
Setoguchi, R., Matsui, Y., & Mouri, K. (2015) · European Journal of Immunology · doi:10.1002/eji.201445086 · Cited by 21 · see citing works
Peroxiredoxin II Regulates Effector and Secondary Memory CD8<sup>+</sup>T Cell Responses
Michalek, R. D., Crump, K. E., Weant, A. E., Hiltbold, E. M., Juneau, D. G., Moon, E.-Y., Yu, D.-Y., Poole, L. B., & Grayson, J. M. (2012) · Journal of Virology · doi:10.1128/jvi.01559-12 · Cited by 17 · see citing works
Immune memory: the basics and how to trigger an efficient long-term immune memory
Beverley, P. C. L. (2010) · Journal of Comparative Pathology · doi:10.1016/j.jcpa.2009.09.008 · Cited by 4 · see citing works
- Authors
- Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L.-S., Jones, R. G., & Choi, Y.
- Affiliations
- University of Pennsylvania (US)
- McGill University (CA)
- Corresponding author
- Choi, Yongwon
- ORCID
- Venue
- Nature
- Published
- 2009-06-03
- Volume
- 460
- Issue
- 7251
- Pages
- 103-107
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2803086
- OpenAlex
- W1999324987
- Cited by
- 1,559
- References
- 41
- Citations by year
- 2026: 68 · 2025: 72 · 2024: 89 · 2023: 120 · 2022: 121 · 2021: 120 · 2020: 135 · 2019: 100 · 2018: 98 · 2017: 101 · 2016: 85 · 2015: 93 · 2014: 75 · 2013: 78 · 2012: 73
- FWCI
- 29.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases (R01AI064909)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD8+ T cell memory, fatty acid metabolism, TRAF6, mitochondrial fatty acid oxidation, AMPK, glucose metabolism, effector T cells, memory T cells, metformin, cancer vaccines, T cell metabolism, infection immunity
- MeSH terms
- Animals, Fatty Acids, Hypoglycemic Agents, Immunologic Memory, Listeriosis, Listeria monocytogenes, Metformin, Mice, Inbred C57BL, CD8-Positive T-Lymphocytes, TNF Receptor-Associated Factor 6, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-cbl, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
