mTOR regulates memory CD8 T-cell differentiation

Araki, Koichi; Turner, Alexandra P.; Shaffer, Virginia Oliva; Gangappa, Shivaprakash; Keller, Susanne A.; Bachmann, Martin F.; Larsen, Christian P.; Ahmed, Rafi

doi:10.1038/nature08155

Cited by 1,575T-cell and B-cell ImmunologyImmunotherapy and Immune ResponsesPI3K/AKT/mTOR signaling in cancer

mTOR regulates memory CD8 T-cell differentiation

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Araki, Koichi, Turner, Alexandra P., Shaffer, Virginia Oliva, Gangappa, Shivaprakash, Keller, Susanne A., Bachmann, Martin F., Larsen, Christian P., Ahmed, Rafi·2009·Nature

DOI 10.1038/nature08155PMC PMC2710807

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Abstract

Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.

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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 [20]

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mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555 · see citing works
The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation
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“, 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).”
Background
Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets
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
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L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity
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HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells
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Transcriptional 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
mTOR is a key modulator of ageing and age-related disease
Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013) · Nature · doi:10.1038/nature11861 · Cited by 1,676 · see citing works
The cancer metabolic reprogramming and immune response
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Fueling 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
Metabolic 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
Regulation 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
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
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Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation
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
Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8 + T Cell Exhaustion
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).”
Background
Metabolism of immune cells in cancer
Leone, R. D., & Powell, J. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-020-0273-y · Cited by 877 · see citing works
Regulation of Immune Responses by mTOR
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Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells
Skon, C. N., Lee, J.-Y., Anderson, K. G., Masopust, D., Hogquist, K. A., & Jameson, S. C. (2013) · Nature Immunology · doi:10.1038/ni.2745 · Cited by 817 · see citing works
mTOR inhibition improves immune function in the elderly
Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., Lonetto, M. A., Maecker, H. T., Kovarik, J., Carson, S., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3009892 · Cited by 786 · see citing works
Hallmarks of T cell aging
Mittelbrunn, M., & Kroemer, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00927-z · Cited by 702 · see citing works
mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells
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Metabolites and the Tumour Microenvironment: From Cellular Mechanisms to Systemic Metabolism
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The mTOR Kinase Determines Effector versus Memory CD8+ T Cell Fate by Regulating the Expression of Transcription Factors T-bet and Eomesodermin
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
mTOR as Regulator of Lifespan, Aging, and Cellular Senescence: A Mini-Review
Weichhart, T. (2018) · Gerontology · doi:10.1159/000484629 · Cited by 596 · see citing works
PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells
Finlay, D. K., Rosenzweig, E., Sinclair, L. V., Feijoo-Carnero, C., Hukelmann, J. L., Rolf, J., Panteleyev, A. A., Okkenhaug, K., & Cantrell, D. A. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20112607 · Cited by 596 · 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
Sterol regulatory element–binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity
Kidani, 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
Rapalogs and mTOR inhibitors as anti-aging therapeutics
Lamming, D. W., Ye, L., Sabatini, D. M., & Baur, J. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64099 · Cited by 531 · see citing works
The quest to slow ageing through drug discovery
Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0067-7 · Cited by 468 · see citing works
The CDK4/6 Inhibitor Abemaciclib Induces a T Cell Inflamed Tumor Microenvironment and Enhances the Efficacy of PD-L1 Checkpoint Blockade
Schaer, D. A., Beckmann, R. P., Dempsey, J. A., Huber, L., Forest, A., Amaladas, N., Li, Y., Wang, Y. C., Rasmussen, E. R., Chin, D., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.053 · Cited by 469 · see citing works
Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance
Maldonado, R. A., LaMothe, R. A., Ferrari, J. D., Zhang, A.-H., Rossi, R. J., Kolte, P. N., Griset, A. P., O’Neil, C., Altreuter, D. H., Browning, E., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408686111 · Cited by 441 · 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
Immunogenicity and toxicity of AAV gene therapy
Ertl, H. C. J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.975803 · Cited by 402 · see citing works
p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells
Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., Puleston, D. J., Watson, A. S., Simon, A. K., Tooze, S. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75051 · Cited by 389 · see citing works
Autophagy is a critical regulator of memory CD8+ T cell formation
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Aging and Immune Function: Molecular Mechanisms to Interventions
Ponnappan, S., & Ponnappan, U. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3228 · Cited by 339 · see citing works
Heterogeneity in the Differentiation and Function of CD8+ T Cells
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The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells
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
Self-citation
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
Leptin as an immunomodulator
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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
The cytotoxic T cell proteome and its shaping by the kinase mTOR
Hukelmann, J. L., Anderson, K. E., Sinclair, L. V., Grzes, K. M., Murillo, A. B., Hawkins, P. T., Stephens, L. R., Lamond, A. I., & Cantrell, D. A. (2016) · Nature Immunology · doi:10.1038/ni.3314 · Cited by 249 · 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
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
Spermidine 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
Immunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212 · see citing works
mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging
Perl, A. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12756 · Cited by 218 · 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
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Roles of mTOR complexes in the kidney: implications for renal disease and transplantation
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Authors: Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., Larsen, C. P., & Ahmed, R.
Affiliations: Emory University (US)
Corresponding author: Ahmed, Rafi
ORCID: Araki, Koichi
Turner, Alexandra P.
Shaffer, Virginia Oliva
Gangappa, Shivaprakash
Bachmann, Martin F.
Larsen, Christian P.
Ahmed, Rafi
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2009-06-21
Volume: 460
Issue: 7251
Pages: 108-112
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature08155
PMC: PMC2710807
OpenAlex: W2064876347
Cited by: 1,575
References: 116
Citations by year: 2026: 50 · 2025: 63 · 2024: 78 · 2023: 89 · 2022: 112 · 2021: 98 · 2020: 104 · 2019: 83 · 2018: 98 · 2017: 78 · 2016: 95 · 2015: 113 · 2014: 104 · 2013: 104 · 2012: 107
FWCI: 43.35
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (n01ai30048-10-0-1, n01ai50025-5-0-0)
National Institute of Allergy and Infectious Diseases (R37AI040519, R01AI139675, N01 AI030048, N01 AI050025, AI030048, AI040519, R01AI073707, R37AI030048, R01AI030048)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: mTOR, CD8+ T cell differentiation, memory T cells, rapamycin, PI3K/AKT/mTOR signalling, mTORC1, raptors, FKBP12, virus-specific T cells, lymphocytic choriomeningitis virus, vaccine adjuvants, modified vaccinia Ankara, non-human primates
MeSH terms: Mechanistic Target of Rapamycin Complex 1, Animals, Antigens, Viral, Cell Differentiation, Cells, Cultured, Immunologic Memory, Lymphocytic choriomeningitis virus, Macaca mulatta, Mice, Inbred C57BL, Protein Kinases, Proteins, Transcription Factors, CD8-Positive T-Lymphocytes, Lymphocyte Count, Sirolimus, Multiprotein Complexes, Mice, TOR Serine-Threonine Kinases

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