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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
Open accessAbstract
The mechanisms underpinning integration of instructions that program naive CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that interleukin-12 (IL-12) enhanced and sustained antigen and costimulatory molecule (B7.1)-induced mTOR kinase activity in naive CD8+ (OT-I) T cells via phosphoinositide 3-kinase and STAT4 transcription factor pathways. Blocking mTOR activity by rapamycin reversed IL-12-induced effector functions because of loss of persistent expression of the transcription factor T-bet. Rapamycin treatment of IL-12-conditioned OT-I cells promoted persistent Eomesodermin expression and produced memory cell precursors that demonstrated enhanced sustenance and antigen-recall responses upon adoptive transfer. The memory cell precursors showed greater tumor efficacy than IL-12-conditioned effector OT-I cells. These results identify mTOR as the central regulator of transcriptional programs that determine effector and/or memory cell fates in CD8+ T cells. Targeting mTOR activity offers new opportunities to regulate CD8+ T cell-mediated immunity.
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“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 [19]
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TOR signaling in growth and metabolism
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“It is possible that mTOR, which has been shown to tether several transcriptional factors (both activators and repressors) (Wullschleger et al., 2006) may regulate T-bet expression based on its activity.”
BackgroundInfluentialUpstream and downstream of mTOR
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“Although the kinase mTOR has been implicated as an integrator of various extracellular signals and a sensor for internal energy levels for determination of cell fate (Hay and Sonenberg, 2004), the role for mTOR in integrating instructions that program naive CD8 T cells for type I effector differentiation is unclear.”
BackgroundA Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment
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BackgroundCancer regression in patients after transfer of genetically engineered lymphocytes
Morgan, R. A., Dudley, M. E., Wunderlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., Royal, R. E., Topalian, S. L., Kammula, U. S., Restifo, N. P., et al. (2006) · Science · doi:10.1126/science.1129003 · Cited by 2,603 · cited 2×
“Rapamycin-Treated IL-12-Conditioned OT-I Cells Demonstrate Augmented Tumor Efficacy The use of ex vivo generated tumor-antigen-specific effector CD8 T cells in adoptive cell transfer (ACT) has produced tumor regressions in the clinical setting (Morgan et al., 2006).”
BackgroundTOR, a Central Controller of Cell Growth
Schmelzle, T., & Hall, M. N. (2000) · Cell · doi:10.1016/s0092-8674(00)00117-3 · Cited by 1,914 · cited 2×
“In agreement, with the reported role for mTOR in regulating cell size (Schmelzle and Hall, 2000) and the expression of L-type amino acid transporter (CD98) (Cornish et al.”
BackgroundLineage relationship and protective immunity of memory CD8 T cell subsets
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“Several transcription factors have been shown to coordinate and regulate the balance between long-lived memory and terminally differentiated effector CD8+ T cells (Intlekofer et al., 2005; Joshi et al., 2007; Welsh, 2009).”
BackgroundInfluentialInterleukin-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 · cited 2×
“…node homing) (Wherry et al., 2003), CD69 (lymph node retention) (Shiow et al., 2006), CD127 (IL-7Ra; essential for memory T cell maintenance) (Schluns et al., 2000), CD122 (IL-15Rb and essential for memory CD8+ T cell homeostatic renewal) (Schluns et al., 2002), KLRG1 (inversely corelated…”
BackgroundmTOR regulates memory CD8 T-cell differentiation
Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., Larsen, C. P., & Ahmed, R. (2009) · Nature · doi:10.1038/nature08155 · Cited by 1,575
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“A previous study showed that suppressing mTOR signaling during the antigen-specific maturation of CD8 T cells reduced their CTL activity with decreased IFN-g and Gr B [50].”
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“inhibitor rapamycin can promote the formation of memory CD8+ T cells by regulating the expression of the transcription factors T-bet and eomesodermin, thereby enhancing antitumor function (70).”
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The influence of mTOR inhibitors on immunity and the relationship to post-transplant malignancy
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“…al., 2010; Chi, 2012; Martin et al., 2021). mTOR also mediates insulin-induced alteration of metabolic rates and immune responses in myeloid cells (Ratter et al., 2021), and mTOR mediates age-associated microglial priming and neurodegeneration (Keane et al., 2021), suggesting that insulin-induced…”
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“Recently, mTORC1 signaling has been shown to be required for Th1 differentiation (6, 7) likely by inducing Tbet expression (8).”
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“IL-7 receptor (IL-7R) signaling promotes induction of the T-box transcription factor 21 (T-bet) in these cells, which induces CD122 (a component of the IL-15R) and thus sensitizes the cells to the effects of IL-15 to induce the T-box transcription factor eomesodermin (Eomes) [16].”
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Sully, K., Akinduro, O., Philpott, M. P., Naeem, A. S., Harwood, C. A., Reeve, V. E., O’Shaughnessy, R. F. L., & Byrne, C. R. (2012) · Oncogene · doi:10.1038/onc.2012.338 · Cited by 29
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Metabolism of T Lymphocytes in Health and Disease
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“The ratio between these molecules, rather than their expression level therefore appears to determine whether a cell obtains a memory or effector cell phenotype (46).”
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“, 2010) or in contexts with designed antigen-presenting cells and with cytokines providing inflammatory (IL-12) or survival (IL-7 and IL-15) signals that may predominate over and potentially obscure early TCR signals (Intlekofer et al., 2005; Rao et al., 2010).”
BackgroundInfluentialThe smallest unit: effector and memory CD8+ T cell differentiation on the single cell level
Buchholz, V. R., Gräf, P., & Busch, D. H. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00031 · Cited by 27
“…T cells through conserving their longevity, quiescence and selfrenewal capacity (Betz and Müller, 1998; Castellino and Germain, 2007; Hand et al., 2010; Rao et al., 2010, 2012; Cui et al., 2011; Ji et al., 2011; Siegel et al., 2011; Yang et al., 2011; Kim et al., 2012; Thaventhiran et al., 2012).”
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“While the inhibition of mTOR promotes generation of CD8 memory T cells [62], at the same time it induces cell death by necrosis in the culture of U-937 monocytes [63], which may trigger an auto-inflammatory response.”
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“Thus, inhibition of mTORC1 with rapamycin may be most effective at enhancing antitumor CD8þ T-cell immunity when employed at low doses that do not ablate the initial expansion of effector cells (28) or when it is curtailed early following priming to maximize secondary effector responses (18, 31).”
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“Additional molecules that target metabolic pathways including the use the mammalian target of rapamycin (mTOR) inhibitor rapamycin [56] or AKT inhibitors [57] have been shown to promote the function of minimally differentiated memory cells.”
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“Furthermore, IL-12 treatment activates central signaling pathways that regulate actin depletion and recovery at the IS (4, 8, 26, 27, 38) and are required for cytoskeletal force generation in CTLs (29, 31).”
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“Retroviral over-expression of pri-miRNAs revealed that miR-139-3p can lead to downregulation of perforin and the transcription factor EOMES, while miR-150 indirectly regulated expression of the high affinity interleukin (IL)-2 receptor, CD25 (38). miR-29 is also down-regulated in response to T cell activation, and is…”
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Hoshii, T., Matsuda, S., & Hirao, A. (2014) · The Journal of Biochemistry · doi:10.1093/jb/mvu037 · Cited by 25
Sensitivity to Restimulation-Induced Cell Death Is Linked to Glycolytic Metabolism in Human T Cells
Larsen, S. E., Bilenkin, A., Tarasenko, T. N., Arjunaraja, S., Stinson, J. R., McGuire, P. J., & Snow, A. L. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1601218 · Cited by 24
“reprogramming may work in part by allowing greater numbers of T cells to escape RICD (12, 41).”
BackgroundMejia, P., Trevino-Villarreal, J. H., Reynolds, J. S., Niz, M. D., Thompson, A., Marti, M., & Mitchell, J. R. (2017) · Malaria Journal · doi:10.1186/s12936-017-2092-5 · Cited by 27
Mechanisms That Regulate Peripheral Immune Responses to Control Organ-Specific Autoimmunity
Hoyne, G. F. (2011) · Clinical and Developmental Immunology · doi:10.1155/2011/294968 · Cited by 24
“, Th1, Th2 Th17) [89], CD8+ T cell memory [90, 91], as well as the differentiation of Treg cells in the periphery [79] and lymphocyte trafficking [92].”
BackgroundPleiotropic effects of antibiotics on T cell metabolism and T cell-mediated immunity
Franz, T. J., Negele, J., Bruno, P., Böttcher, M., Mitchell-Flack, M., Reemts, L., Krone, A., Mougiakakos, D., Müller, A. J., Zautner, A. E., et al. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.975436 · Cited by 24
“Hence, rapamycin treatment in CD4 OT-II T cells significantly reduced their activation (measured as decreased CD44 expression) (Rao et al., 2010).”
BackgroundBreakdown in Repression of IFN-γ mRNA Leads to Accumulation of Self-Reactive Effector CD8+ T Cells
Chang, P.-P., Lee, S. K., Hu, X., Davey, G. M., Duan, G., Cho, J.-H., Karupiah, G., Sprent, J., Heath, W. R., Bertram, E. M., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102432 · Cited by 23
“development through its ability to sustain T-bet expression (15).”
BackgroundCapone, S., Brown, A., Hartnell, F., Sorbo, M. D., Traboni, C., Vassilev, V. B., Colloca, S., Nicosia, A., Cortese, R., Folgori, A., et al. (2020) · npj Vaccines · doi:10.1038/s41541-020-00240-0 · Cited by 24
Deciphering the deterministic role of TCR signaling in T cell fate determination
Qin, Z., & Xu, T. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1562248 · Cited by 30
Nicotine Inhibits Memory CTL Programming
Sun, Z., Smyth, K., Garcia, K. Y., Mattson, E., Li, L., & Xiao, Z. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068183 · Cited by 22
“More importantly, IL-12 can program CTLs to become memory cells [22,24], and this IL-12-driven memory programming can be upregulated by inhibition of the mammalian target of rapamycin (mTOR) [24,25], indicating utilization of a major pathway of cell growth regulation [26,27].”
BackgroundMethodResultInfluentialCD8 T Cells Recruited Early in Mouse Polyomavirus Infection Undergo Exhaustion
Wilson, J. J., Pack, C. D., Lin, E. E., Frost, E. L., Albrecht, J. A., Hadley, A., Hofstetter, A. R., Tevethia, S. S., Schell, T. D., & Lukacher, A. E. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103727 · Cited by 22
“Therefore, while T-bet levels were similar, consistent with each memory population retaining an effector differentiation state, increased Eomes expression may explain increased survival and functional competence of the persistent infected-recruited cells (29, 30).”
BackgroundmTORC1 regulates CD8+ T-cell glucose metabolism and function independently of PI3K and PKB
Finlay, D. K. (2013) · Biochemical Society Transactions · doi:10.1042/bst20120359 · Cited by 23
Nunoya, J.-I., Masuda, M., Ye, C., & Su, L. (2019) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2019.03.002 · Cited by 22
Mitochondrial Inhibition: a Treatment Strategy in Cancer?
Bueno, M. J., Ruiz-Sepulveda, J. L., & Quintela-Fandiño, M. (2021) · Current Oncology Reports · doi:10.1007/s11912-021-01033-x · Cited by 22
Schurich, A., & Henson, S. M. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00468 · Cited by 23
“Blockade of mTOR by rapamycin led to inhibition of IL-12 induced expression of the transcription factor T-bet and skewed the CD8 response toward eomesodermin dependent memory formation (53).”
BackgroundSetoguchi, R., Matsui, Y., & Mouri, K. (2015) · European Journal of Immunology · doi:10.1002/eji.201445086 · Cited by 21
Wei, Z., Li, P., He, R., Liu, H., Liu, N., Xia, Y., Bi, G., Du, Q., Xia, M., Pei, L., et al. (2019) · Cellular and Molecular Immunology · doi:10.1038/s41423-019-0293-2 · Cited by 21
Karl, F., Liang, C., Loschinski, R., Stoll, A., Flamann, C., Richter, S., Lischer, C., Völkl, S., Jacobs, B., Böttcher, M., et al. (2023) · Blood · doi:10.1182/blood.2022017267 · Cited by 23
Multi-layered epigenetic mechanisms contribute to transcriptional memory in T lymphocytes
Dunn, J., McCuaig, R., Tu, W. J., Hardy, K., & Rao, S. (2015) · BMC Immunology · doi:10.1186/s12865-015-0089-9 · Cited by 23
“Loss of Foxo1 is associated with reduced transcription of promemory transcription factors (such as Eomesodermins, Bcl-6, T-bet), as well as down-regulation of the lymph node-homing molecule Klf-2 (critical for TCM cell function) [69-72].”
Backgroundde Souza, A. P. D., de Freitas, D. N., Fernandes, K. E. A., da Cunha, M. D., Fernandes, J. L. A., Gassen, R. B., Fazolo, T., Pinto, L. A., Scotta, M. C., Mattiello, R., et al. (2015) · Clinical & Experimental Immunology · doi:10.1111/cei.12720 · Cited by 21
The Role and Regulation of mTOR in T-Lymphocyte Function
O’Brien, T. F., & Zhong, X. (2012) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0171-4 · Cited by 22
“However, when stimulated in the presence of rapamycin, OT-I CD8+ T cells exhibited curtailed expression of T-bet, and enhanced expression of eomesodermin (Rao et al. 2010).”
Sensing the immune microenvironment to coordinate T cell metabolism, differentiation & function
Heikamp, E., & Powell, J. D. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.12.003 · Cited by 21
Schmueck‐Henneresse, M., Fischer, A. M., Hammoud, B., Brestrich, G., Fuehrer, H., Luu, S.-H., Mueller, K., Babel, N., Volk, H., & Reinke, P. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103763 · Cited by 21
“Rapamycin seems to prolong the survival of Ag-specific T cells (18, 19).”
BackgroundRegulation of Memory CD8+ T Cell Differentiation by MicroRNAs
Zhang, Z., Zhang, C., Li, F., Zhang, B., & Zhang, Y. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000491532 · Cited by 21
Villegas-Méndez, A., Khandelwal, G., McGowan, L. M., Dookie, R. S., Haley, M., George, C. L., Sims, D., Lord, G. M., Sinclair, L. V., Jenner, R. G., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.2000450 · Cited by 22
“We have shown, in agreement with previous studies (54, 55), that mTOR is required to promote T-bet expression during the initial activation of T cells.”
ResultKrishna, S., Yang, J., Wang, H., Qiu, Y., & Zhong, X. (2014) · Infection and Immunity · doi:10.1128/iai.01816-14 · Cited by 20
Metabolism in Immune Cell Differentiation and Function
Chapman, N. M., Shrestha, S., & Chi, H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-94-024-1170-6_1 · Cited by 22
Claiborne, M. D., Sengupta, S., Zhao, L., Arwood, M. L., Sun, I.-M., Wen, J., Thompson, E. A., Mitchell-Flack, M., Laiho, M., & Powell, J. D. (2022) · Science Immunology · doi:10.1126/sciimmunol.abh4271 · Cited by 21
“Upon T cell activation, the phospha tidylinositol 3kinase (PI3K)/Akt/mTOR signaling cascade results in robust mTORC1 activity that is detectable within minutes and returns to baseline by 48 to 72 hours (8).”
BackgroundTSC2 regulates tumor susceptibility to TRAIL‐mediated T‐cell killing by orchestrating mTOR signaling
Lin, C., Traets, J. J. H., Vredevoogd, D. W., Visser, N. L., & Peeper, D. S. (2023) · The EMBO Journal · doi:10.15252/embj.2022111614 · Cited by 19
Dielmann, A., Letsch, A., Nonnenmacher, A., Miller, K., Keilholz, U., & Busse, A. (2016) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-015-1786-1 · Cited by 19
McQueen, B., Trace, K., Whitman, E., Bedsworth, T., & Barber, A. (2015) · Immunology · doi:10.1111/imm.12563 · Cited by 20
Henriques, A., Silva, C., Santiago, M., Henriques, M. J., Martinho, A., Trindade, H., da Silva, J. A. P., Silva‐Santos, B., & Paiva, A. A. (2016) · Inflammation Research · doi:10.1007/s00011-016-0982-6 · Cited by 19
Dantal, J., & Campone, M. (2016) · Transplantation · doi:10.1097/tp.0000000000001428 · Cited by 20
Fox, A., Harland, K. L., Kedzierska, K., & Kelso, A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01141 · Cited by 18
“Similarly, Eomes induction may promote CCR7 expression because suppression of Eomes upon mTOR induction prevents CCR7 expression (33, 64).”
Self-Regulation of Memory CD8 T Cell Metabolism through Extracellular ATP Signaling
Wanhainen, K. M., Jameson, S. C., & da Silva, H. B. (2019) · Immunometabolism · doi:10.20900/immunometab20190009 · Cited by 21
Rapamycin‐resistant effector T‐cell therapy
Fowler, D. H. (2013) · Immunological Reviews · doi:10.1111/imr.12127 · Cited by 20
“Rapamycin blocked IL-12 (92)- or IL-7 (93)-induced effector CD8 T-cell maturation, with a resultant shift in transcription factor expression from T-bet to eomesodermin and an increase of in vivo memory function and anti-tumor efficacy.”
BackgroundInfluentialGab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8+ T-Cell Activation
Wang, Z., Vaughan, T. Y., Zhu, W., Chen, Y., Fu, G., Medrzycki, M., Nishio, H., Bunting, S. T., Hankey-Giblin, P. A., Nusrat, A., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00486 · Cited by 18
Nicotinamide breaks effector CD8 T cell responses by targeting mTOR signaling
Agliano, F., Karginov, T. A., Ménoret, A., Provatas, A. A., & Vella, A. T. (2022) · iScience · doi:10.1016/j.isci.2022.103932 · Cited by 18
“Specifically, although effector CD8 T cells augment mTOR activity leading to tbet induction and decreasing eomesodermin, memory CD8 T cells show the opposite effect (Araki et al., 2009; Rao et al., 2010).”
BackgroundInfluentialTan, X., Li, Y., Hou, Z., Zhang, M., Li, L., & Wei, J. (2023) · Experimental Cell Research · doi:10.1016/j.yexcr.2023.113647 · Cited by 18
Metadata
- Authors
- Rao, R. R., Li, Q., Odunsi, K., & Shrikant, P. A.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Corresponding author
- Shrikant, Protul A.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 32
- Issue
- 1
- Pages
- 67-78
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5836496
- OpenAlex
- W2059689009
- Cited by
- 656
- References
- 41
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 15 · 2023: 24 · 2022: 41 · 2021: 40 · 2020: 36 · 2019: 38 · 2018: 44 · 2017: 39 · 2016: 43 · 2015: 63 · 2014: 49 · 2013: 66 · 2012: 54
- FWCI
- 25.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA158318, R01CA104645, P30CA016056)
- 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 kinase, CD8+ T cells, T-bet, Eomesodermin, IL-12, phosphatidylinositol 3-kinase, STAT4, rapamycin, naive T cell differentiation, cancer immunotherapy
- MeSH terms
- T-bet Transcription Factor, Animals, Cell Differentiation, Immunologic Memory, Lymphocyte Activation, Mice, Transgenic, Transduction, Genetic, Signal Transduction, T-Lymphocyte Subsets, Protein Serine-Threonine Kinases, CD8-Positive T-Lymphocytes, T-Box Domain Proteins, Intracellular Signaling Peptides and Proteins, Mice, TOR Serine-Threonine Kinases
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