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.
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?
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 [19]
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
TOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787 · see citing works
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181 · see citing works
A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment
Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000) · Cell · doi:10.1016/s0092-8674(00)80702-3 · Cited by 3,589 · see citing works
Cancer 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 · see citing works
TOR, a central controller of cell growth.
Schmelzle, T., & Hall, M. (2000) · Cell · doi:10.1016/s0092-8674(00)00117-3 · Cited by 2,044 · see citing works
Lineage relationship and protective immunity of memory CD8 T cell subsets
Wherry, E. J., Teichgräber, V., Becker, T. C., Masopust, D., Kaech, S. M., Antia, R., von Andrian, U. H., & Ahmed, R. (2003) · Nature Immunology · doi:10.1038/ni889 · Cited by 1,864 · 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
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
mTOR 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 · see citing works
Enhancing CD8 T-cell memory by modulating fatty acid metabolism
Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L.-S., Jones, R. G., & Choi, Y. (2009) · Nature · doi:10.1038/nature08097 · Cited by 1,559 · see citing works
Plasticity of CD4+ T Cell Lineage Differentiation
Zhou, L., Chong, M. M. W., & Littman, D. R. (2009) · Immunity · doi:10.1016/j.immuni.2009.05.001 · Cited by 1,551 · see citing works
TH-17 cells in the circle of immunity and autoimmunity
Bettelli, E., Oukka, M., & Kuchroo, V. K. (2007) · Nature Immunology · doi:10.1038/ni0407-345 · Cited by 1,503 · see citing works
mTOR differentially regulates effector and regulatory T cell lineage commitment
Delgoffe, G. M., Kole, T., Zheng, Y., Zarek, P. E., Matthews, K., Xiao, B., Worley, P., Kozma, S., & Powell, J. (2009) · Immunity · doi:10.1016/j.immuni.2009.04.014 · Cited by 1,293 · see citing works
Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin
Intlekofer, A. M., Takemoto, N., Wherry, E. J., Longworth, S. A., Northrup, J. T., Palanivel, V., Mullen, A. C., Gasink, C. R., Kaech, S. M., Miller, J. D., et al. (2005) · Nature Immunology · doi:10.1038/ni1268 · Cited by 1,257 · see citing works
CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs
Shiow, L. R., Rosen, D. B., Brdičková, N., Xu, Y., An, J., Lanier, L. L., Cyster, J. G., & Matloubian, M. (2006) · Nature · doi:10.1038/nature04606 · Cited by 1,189 · see citing works
Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells
Gattinoni, L., Zhong, X.-S., Palmer, D. C., Ji, Y., Hinrichs, C. S., Yu, Z., Wrzesinski, C., Boni, A., Cassard, L., Garvin, L. M., et al. (2009) · Nature Medicine · doi:10.1038/nm.1982 · Cited by 1,031 · see citing works
Mammalian TOR: a homeostatic ATP sensor
Dennis, P. B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S. C., & Thomas, G. (2001) · Science · doi:10.1126/science.1063518 · Cited by 962 · see citing works
The Duration of Antigenic Stimulation Determines the Fate of Naive and Effector T Cells
Iezzi, G., Karjalainen, K., & Lanzavecchia, A. (1998) · Immunity · doi:10.1016/s1074-7613(00)80461-6 · Cited by 909 · see citing works
Jacobson, N. G., Szabo, S. J., Weber-Nordt, R., Zhong, Z.-H., Schreiber, R. D., Darnell, J. E., Jr., & MURPHY, K. M. M. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.181.5.1755 · Cited by 673 · see citing works
Kaech, S. M., & Wherry, E. J. (2007) · Immunity · doi:10.1016/j.immuni.2007.08.007 · Cited by 619 · 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
Signal 3 Determines Tolerance versus Full Activation of Naive CD8 T Cells
Curtsinger, J., Lins, D. C., & Mescher, M. F. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021910 · Cited by 510 · see citing works
Rapamycin in transplantation: A review of the evidence
Saunders, R. N., Metcalfe, M. S., & Nicholson, M. L. (2001) · Kidney International · doi:10.1046/j.1523-1755.2001.00460.x · Cited by 466 · see citing works
Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking
Sinclair, L. V., Finlay, D. K., Feijóo, C. G., Cornish, G. H., Gray, A., Ager, A., Okkenhaug, K., Hagenbeek, T. J., Spits, H., & Cantrell, D. A. (2008) · Nature Immunology · doi:10.1038/ni.1603 · Cited by 391 · see citing works
Glucose Availability Regulates IFN-γ Production and p70S6 Kinase Activation in CD8+ Effector T Cells
Cham, C. M., & Gajewski, T. F. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.8.4670 · Cited by 359 · see citing works
Cutting Edge: Increased Expression of Bcl-2 in Antigen-Specific Memory CD8+ T Cells
Grayson, J. M., Zajac, A. J., Altman, J. D., & Ahmed, R. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.8.3950 · Cited by 349 · see citing works
Takemoto, N., Intlekofer, A. M., Northrup, J. T., Wherry, E. J., & Reiner, S. L. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7515 · Cited by 339 · see citing works
Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction
Mullen, A. C., Hutchins, A. S., High, F. A., Lee, H. W., Sykes, K. J., Chodosh, L. A., & Reiner, S. L. (2002) · Nature Immunology · doi:10.1038/ni807 · Cited by 306 · see citing works
A role for mammalian target of rapamycin in regulating T cell activation versus anergy
Zheng, Y., Collins, S. L., Lutz, M. A., Allen, A. N., Kole, T. P., Zarek, P. E., & Powell, J. D. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.4.2163 · Cited by 274 · see citing works
Harris, T. E., & Lawrence, J. C. (2003) · Science s STKE · doi:10.1126/stke.2122003re15 · Cited by 234 · see citing works
Programming for CD8 T Cell Memory Development Requires IL-12 or Type I IFN
Xiao, Z., Casey, K. A., Jameson, S. C., Curtsinger, J., & Mescher, M. F. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803484 · Cited by 209 · see citing works
Agarwal, P., Raghavan, A., Nandiwada, S. L., Curtsinger, J., Bohjanen, P. R., Mueller, D. L., & Mescher, M. F. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900592 · Cited by 203 · see citing works
Differential regulation of T-cell growth by IL-2 and IL-15
Cornish, G. H., Sinclair, L. V., & Cantrell, D. A. (2006) · Blood · doi:10.1182/blood-2005-12-4827 · Cited by 175 · see citing works
Yoo, J. K., Cho, J., Lee, S. W., & Sung, Y. C. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3637 · Cited by 126 · see citing works
Kang, J., Huddleston, S. J., Fraser, J. M., & Khoruts, A. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.1207851 · Cited by 124 · see citing works
The descent of memory T-cell subsets
Lefrançois, L., & Marzo, A. L. (2006) · Nature reviews. Immunology · doi:10.1038/nri1866 · Cited by 114 · see citing works
Temporal Dissection of T-bet Functions
Matsuda, J. L., George, T. C., Hagman, J. R., & Gapin, L. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.6.3457 · Cited by 71 · see citing works
Prlic, M., & Bevan, M. J. (2009) · Nature · doi:10.1038/460041a · Cited by 63 · see citing works
IL-12-Programmed Long-Term CD8+ T Cell Responses Require STAT4
Li, Q., Eppolito, C., Odunsi, K. O., & Shrikant, P. A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.11.7618 · Cited by 56 · see citing works
Self-citationGoldberg, J. D., Shrikant, P. A., & Mescher, M. F. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.1.228 · Cited by 55 · see citing works
Self-citationBlimp Hovers over T Cell Immunity
Welsh, R. M. (2009) · Immunity · doi:10.1016/j.immuni.2009.08.005 · Cited by 39 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
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
T cell metabolism drives immunity
Buck, M. D., O’Sullivan, D., & Pearce, E. L. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20151159 · Cited by 1,190 · see citing works
Delgoffe, G. M., Pollizzi, K. N., Waickman, A. T., Heikamp, E., Meyers, D. J., Horton, M. R., Xiao, B., Worley, P. F., & Powell, J. D. (2011) · Nature Immunology · doi:10.1038/ni.2005 · Cited by 1,111 · see citing works
CD8+ T Cells: Foot Soldiers of the Immune System
Zhang, N., & Bevan, M. J. (2011) · Immunity · doi:10.1016/j.immuni.2011.07.010 · Cited by 1,102 · 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
Immunosenescence: molecular mechanisms and diseases
Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y., & Han, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01451-2 · Cited by 1,023 · 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
Metabolic regulation of immune responses
Ganeshan, K., & Chawla, A. (2014) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032713-120236 · Cited by 926 · see citing works
Interleukin-2 Receptor Signaling: At the Interface between Tolerance and Immunity
Malek, T. R., & Castro, I. (2010) · Immunity · doi:10.1016/j.immuni.2010.08.004 · Cited by 852 · 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
Lastwika, K. J., Wilson, W., Li, Q. K., Norris, J., Xu, H., Ghazarian, S. R., Kitagawa, H., Kawabata, S., Taube, J. M., Yao, S., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-14-3362 · Cited by 785 · see citing works
Self-citationAmino Assets: How Amino Acids Support Immunity
Kelly, B. L., & Pearce, E. L. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.010 · Cited by 653 · see citing works
From Vaccines to Memory and Back
Sallusto, F., Lanzavecchia, A., Araki, K., & Ahmed, R. (2010) · Immunity · doi:10.1016/j.immuni.2010.10.008 · Cited by 631 · see citing works
T memory stem cells in health and disease
Gattinoni, L., Speiser, D. E., Lichterfeld, M. D., & Bonini, C. (2017) · Nature Medicine · doi:10.1038/nm.4241 · Cited by 619 · see citing works
CD8+ T cell metabolism in infection and cancer
Reina-Campos, M., Scharping, N. E., & Goldrath, A. W. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00537-8 · Cited by 574 · see citing works
Metabolic barriers to cancer immunotherapy
DePeaux, K., & Delgoffe, G. M. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00541-y · Cited by 614 · see citing works
Paths to stemness: building the ultimate antitumour T cell
Gattinoni, L., Klebanoff, C. A., & Restifo, N. P. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3322 · Cited by 599 · see citing works
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
Immune-mediated antitumor effect by type 2 diabetes drug, metformin
Eikawa, S., Nishida, M., Mizukami, S., Yamazaki, C., Nakayama, E., & Udono, H. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417636112 · Cited by 553 · see citing works
Understanding subset diversity in T cell memory
Jameson, S. C., & Masopust, D. (2018) · Immunity · doi:10.1016/j.immuni.2018.02.010 · Cited by 523 · see citing works
Klysz, D., Tai, X., Robert, P. A., Craveiro, M., Cretenet, G., Oburoglu, L., Mongellaz, C., Floess, S., Fritz, V., Matias, M. I., et al. (2015) · Science Signaling · doi:10.1126/scisignal.aab2610 · Cited by 522 · see citing works
CD8+ T Cell Exhaustion in Cancer
Dolina, J. S., Budimir, N., Thomas, G. D., & Salek‐Ardakani, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.715234 · Cited by 487 · see citing works
T-bet: a bridge between innate and adaptive immunity
Lazarevic, V., Glimcher, L. H., & Lord, G. M. (2013) · Nature Reviews Immunology · doi:10.1038/nri3536 · Cited by 486 · see citing works
The Mammalian Target of Rapamycin: Linking T Cell Differentiation, Function, and Metabolism
Powell, J. D., & Delgoffe, G. M. (2010) · Immunity · doi:10.1016/j.immuni.2010.09.002 · Cited by 487 · 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
Geissler, E. K., Schnitzbauer, A. A., Zülke, C., Lamby, P. E., Proneth, A., Duvoux, C., Burra, P., Jauch, K.-W., Rentsch, M., Ganten, T. M., et al. (2016) · Transplantation · doi:10.1097/tp.0000000000000965 · Cited by 433 · see citing works
Signaling by the Phosphoinositide 3-Kinase Family in Immune Cells
Okkenhaug, K. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095946 · Cited by 446 · see citing works
Banerjee, A., Gordon, S. M., Intlekofer, A. M., Paley, M., Mooney, E. C., Lindsten, T., Wherry, E. J., & Reiner, S. L. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1002042 · Cited by 429 · 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
Fatty acid metabolism in the regulation of T cell function
Lochner, M., Berod, L., & Sparwasser, T. D. (2015) · Trends in Immunology · doi:10.1016/j.it.2014.12.005 · Cited by 417 · see citing works
The spectrum of T cell metabolism in health and disease
Bantug, G. R., Galluzzi, L., Kroemer, G., & Hess, C. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.99 · Cited by 421 · see citing works
mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation
Pollizzi, K. N., Patel, C. H., Sun, I., Oh, M. H., Waickman, A. T., Wen, J., Delgoffe, G. M., & Powell, J. D. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77746 · Cited by 409 · see citing works
Staron, M. M., Gray, S. M., Marshall, H. D., Parish, I. A., Chen, J. H., Perry, C. J., Cui, G., Li, M. O., & Kaech, S. M. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.013 · Cited by 384 · see citing works
Integrating canonical and metabolic signalling programmes in the regulation of T cell responses
Pollizzi, K. N., & Powell, J. D. (2014) · Nature reviews. Immunology · doi:10.1038/nri3701 · Cited by 379 · see citing works
Metabolic Hallmarks of Tumor and Immune Cells in the Tumor Microenvironment
Renner, K., Singer, K., Koehl, G. E., Geissler, E. K., Peter, K., Siska, P. J., & Kreutz, M. P. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00248 · Cited by 378 · see citing works
Modulating Glycolysis to Improve Cancer Therapy
Chelakkot, C., Chelakkot, V. S., Shin, Y. K., & Song, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032606 · Cited by 378 · see citing works
Saeidi, A., Zandi, K., Cheok, Y. Y., Saeidi, H., Wong, W. F., Lee, C. Y. Q., Cheong, H. C., Yong, Y. K., Larsson, M., & Shankar, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02569 · Cited by 346 · see citing works
Heterogeneity in the Differentiation and Function of CD8+ T Cells
Mittrücker, H.-W., Visekruna, A., & Huber, M. (2014) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-014-0293-y · Cited by 325 · see citing works
Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases
Perl, A. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.172 · Cited by 335 · 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
Graef, P., Buchholz, V. R., Stemberger, C., Flossdorf, M., Henkel, L., Schiemann, M., Drexler, I., Höfer, T., Riddell, S. R., & Busch, D. H. (2014) · Immunity · doi:10.1016/j.immuni.2014.05.018 · Cited by 311 · see citing works
Metabolic adaptation of lymphocytes in immunity and disease
Chapman, N. M., & Chi, H.-B. (2022) · Immunity · doi:10.1016/j.immuni.2021.12.012 · Cited by 263 · see citing works
Li, W., Lu, L., Lu, J., Wang, X., Yang, C., Jin, J., Wu, L., Hong, X., Li, F., Cao, D., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay9013 · Cited by 305 · 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
Yang, K., Neale, G. A. M., Green, D. R., He, W., & Chi, H. (2011) · Nature Immunology · doi:10.1038/ni.2068 · Cited by 294 · see citing works
Rao, R. R., Li, Q., Bupp, M. G., & Shrikant, P. A. (2012) · Immunity · doi:10.1016/j.immuni.2012.01.015 · Cited by 293 · see citing works
Self-citationMetabolic and Epigenetic Coordination of T Cell and Macrophage Immunity
Phan, A. T., Goldrath, A. W., & Glass, C. K. (2017) · Immunity · doi:10.1016/j.immuni.2017.04.016 · Cited by 291 · see citing works
Generation of effector CD8 + T cells and their conversion to memory T cells
Cui, W., & Kaech, S. M. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00926.x · Cited by 287 · see citing works
Schenk, U., Frascoli, M., Proietti, M., Geffers, R., Traggiai, E., Buer, J., Ricordi, C., Westendorf, A. M., & Grassi, F. (2011) · Science Signaling · doi:10.1126/scisignal.2001270 · Cited by 286 · see citing works
Klebanoff, C. A., Gattinoni, L., & Restifo, N. P. (2012) · Journal of Immunotherapy · doi:10.1097/cji.0b013e31827806e6 · Cited by 276 · see citing works
Metabolic control of regulatory T cell development and function
Zeng, H., & Chi, H. (2014) · Trends in Immunology · doi:10.1016/j.it.2014.08.003 · Cited by 275 · see citing works
Macintyre, A. N., Finlay, D. K., Preston, G., Sinclair, L. V., Waugh, C. M., Tamas, P., Feijóo, C. G., Okkenhaug, K., & Cantrell, D. A. (2011) · Immunity · doi:10.1016/j.immuni.2011.01.012 · Cited by 274 · see citing works
Insulin Receptor-Mediated Stimulation Boosts T Cell Immunity during Inflammation and Infection
Tsai, S., Clemente-Casares, X., Zhou, A. C., Lei, H., Ahn, J. J., Chan, Y. T., Choi, O., Luck, H., Woo, M., Dunn, S. E., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.08.003 · Cited by 272 · 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
Signaling networks in immunometabolism
Saravia, J., Raynor, J. L., Chapman, N. M., Lim, S. A., & Chi, H. (2020) · Cell Research · doi:10.1038/s41422-020-0301-1 · Cited by 252 · see citing works
Lazarevic, V., & Glimcher, L. H. (2011) · Nature Immunology · doi:10.1038/ni.2059 · Cited by 248 · see citing works
Cellular networks controlling T cell persistence in adoptive cell therapy
Chan, J. D., Lai, J., Slaney, C. Y., Kallies, A., Beavis, P. A., & Darcy, P. K. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00539-6 · Cited by 242 · 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
Heterogeneity in Cancer Metabolism: New Concepts in an Old Field
Gentric, G., Mieulet, V., & Mechta‐Grigoriou, F. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6750 · Cited by 237 · see citing works
Targeting memory T cell metabolism to improve immunity
Corrado, M., & Pearce, E. L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148546 · Cited by 234 · see citing works
Interferon Regulatory Factor 4 Sustains CD8+ T Cell Expansion and Effector Differentiation
Yao, S., Buzo, B. F. D., Pham, D., Jiang, L., Taparowsky, E. J., Kaplan, M. H., & Sun, J. (2013) · Immunity · doi:10.1016/j.immuni.2013.10.007 · Cited by 236 · 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
Pollizzi, K. N., Sun, I., Patel, C. H., Lo, Y.-C., Oh, M. H., Waickman, A. T., Tam, A. J., Blosser, R. L., Wen, J., Delgoffe, G. M., et al. (2016) · Nature Immunology · doi:10.1038/ni.3438 · Cited by 231 · see citing works
Differentiation of CD8 memory T cells depends on Foxo1
Michelini, R. H., Doedens, A. L., Goldrath, A. W., & Hedrick, S. Μ. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20130392 · Cited by 228 · see citing works
The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues
Kok, L., Masopust, D., & Schumacher, T. N. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00590-3 · Cited by 230 · see citing works
Targeting lysosomes in human disease: from basic research to clinical applications
Cao, M., Luo, X., Wu, K., & He, X. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00778-y · Cited by 225 · see citing works
Metabolism, migration and memory in cytotoxic T cells
Finlay, D. K., & Cantrell, D. A. (2011) · Nature reviews. Immunology · doi:10.1038/nri2888 · Cited by 220 · see citing works
Metabolism of activated T lymphocytes
Maciolek, J. A., Pasternak, J. A., & Wilson, H. L. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.01.006 · Cited by 224 · see citing works
mTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment
Mafi, S., Mansoori, B., Taeb, S., Sadeghi, H., Abbasi, R., Cho, W. C. S., & Rostamzadeh, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.774103 · Cited by 225 · see citing works
Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy
Gupta, S., Roy, A., & Dwarakanath, B. S. R. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00068 · Cited by 218 · see citing works
Iborra, S., Martínez‐López, M., Khouili, S. C., Enamorado, M., Cueto, F. J., Conde‐Garrosa, R., del Fresno, C., & Sancho, D. (2016) · Immunity · doi:10.1016/j.immuni.2016.08.019 · Cited by 217 · see citing works
Ma, R., Ji, T., Zhang, Y., Dong, W., Chen, X., Xu, P., Chen, D., Liang, X., Yin, X., Liu, Y., et al. (2017) · Nature Cell Biology · doi:10.1038/s41556-017-0002-2 · Cited by 207 · see citing works
Phan, A. T., Doedens, A. L., Palazón, A., Tyrakis, P. A., Cheung, K. P., Johnson, R. S., & Goldrath, A. W. (2016) · Immunity · doi:10.1016/j.immuni.2016.10.017 · Cited by 201 · see citing works
Chimeric antigen receptor T cell persistence and memory cell formation
McLellan, A. D., & Rad, S. M. A. H. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12254 · Cited by 209 · see citing works
Regulation of T cells by mTOR: the known knowns and the known unknowns
Pollizzi, K. N., & Powell, J. D. (2014) · Trends in Immunology · doi:10.1016/j.it.2014.11.005 · Cited by 196 · see citing works
mTOR signaling in the differentiation and function of regulatory and effector T cells
Zeng, H., & Chi, H. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.04.005 · Cited by 194 · see citing works
NFATc1 controls the cytotoxicity of CD8+ T cells
Klein‐Hessling, S., Muhammad, K., Klein, M., Pusch, T., Rudolf, R., Flöter, J., Qureischi, M., Beilhack, A., Vaeth, M., Kummerow, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00612-6 · Cited by 193 · see citing works
Keating, R., Hertz, T., Wehenkel, M., Harris, T. L., Edwards, B. A., McClaren, J. L., Brown, S. A., Surman, S. L., Wilson, Z., Bradley, P. H., et al. (2013) · Nature Immunology · doi:10.1038/ni.2741 · Cited by 191 · see citing works
Duraiswamy, J., Turrini, R., Minasyan, A., Barras, D., Crespo, I., Grimm, A. J., Casado, J., Genolet, R., Benedetti, F., Wicky, A. M., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.10.008 · Cited by 191 · see citing works
Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection
Tu, W., & Rao, S. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.02111 · Cited by 189 · see citing works
Bcl-6 directly represses the gene program of the glycolysis pathway
Oestreich, K. J., Read, K. A., Gilbertson, S. E., Hough, K. P., McDonald, P. W., Krishnamoorthy, V., & Weinmann, A. S. (2014) · Nature Immunology · doi:10.1038/ni.2985 · Cited by 189 · see citing works
mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions
Huang, H., Long, L., Zhou, P., Chapman, N. M., & Chi, H. (2020) · Immunological Reviews · doi:10.1111/imr.12845 · Cited by 193 · see citing works
Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin
Curran, M. A., Geiger, T. L., Montalvo-Ortiz, W., Kim, M., Reiner, S. L., Al‐Shamkhani, A., Sun, J. C.-Y., & Allison, J. P. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121190 · Cited by 187 · see citing works
Role of PI3K/Akt signaling in memory CD8 T cell differentiation
Kim, E. H., & Suresh, M. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00020 · Cited by 181 · see citing works
Headen, D. M., Woodward, K. B., Coronel, M. M., Shrestha, P., Weaver, J. D., Zhao, H., Tan, M., Hunckler, M. D., Bowen, W. S., Johnson, C. T., et al. (2018) · Nature Materials · doi:10.1038/s41563-018-0099-0 · Cited by 175 · see citing works
Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion
Ferris, R. L., Lu, B., & Kane, L. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400557 · Cited by 169 · see citing works
Pathogen induced inflammatory environment controls effector and memory CD8+ T cell differentiation
Obar, J., Jellison, E., Sheridan, B., Blair, D., Pham, Q.-M., Zickovich, J. M., & Lefrançois, L. (2011) · Journal of Immunology · doi:10.4049/jimmunol.1102335 · Cited by 193 · see citing works
Avery, L., Filderman, J. N., Szymczak-Workman, A. L., & Kane, L. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1712107115 · Cited by 166 · see citing works
T‐bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1
Zhang, J., Marotel, M., Fauteux‐Daniel, S., Mathieu, A., Viel, S., Marçais, A., & Walzer, T. (2018) · European Journal of Immunology · doi:10.1002/eji.201747299 · Cited by 167 · see citing works
Li, Q., Rao, R. R., Araki, K., Pollizzi, K. N., Odunsi, K. O., Powell, J. D., & Shrikant, P. A. (2011) · Immunity · doi:10.1016/j.immuni.2011.04.006 · Cited by 160 · see citing works
Self-citationZhang, Z., Li, F., Tian, Y., Cao, L., Gao, Q., Zhang, C., Zhang, K., Shen, C., Ping, Y., Maimela, N. R., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901213 · Cited by 159 · see citing works
Signal Integration by Akt Regulates CD8 T Cell Effector and Memory Differentiation
Kim, E. H., Sullivan, J. A., Plisch, E. H., Tejera, M. M., Jatzek, A., Choi, K. Y., & Suresh, M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103568 · Cited by 157 · see citing works
Adoptive immunotherapy for cancer
Ruella, M., & Kalos, M. (2014) · Immunological Reviews · doi:10.1111/imr.12136 · Cited by 78 · see citing works
The evolving role of tissue-resident memory T cells in infections and cancer
Yenyuwadee, S., Lopez, J. L. S.-T., Shah, R., Rosato, P. C., & Boussiotis, V. A. (2022) · Science Advances · doi:10.1126/sciadv.abo5871 · Cited by 151 · see citing works
Miyauchi, S., Kim, S. S., Pang, J., Gold, K. A., Gutkind, J. S., Califano, J. A., Mell, L. K., Cohen, E. E. W., & Sharabi, A. B. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0871 · Cited by 149 · see citing works
Sun, D.-Y., Hu, Y., Li, X., Peng, J., Dai, Z., & Wang, S. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113392 · Cited by 150 · 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
Metabolic challenges and interventions in CAR T cell therapy
Peng, J.-J., Wang, L., Li, Z., Ku, C., & Ho, P. (2023) · Science Immunology · doi:10.1126/sciimmunol.abq3016 · Cited by 150 · see citing works
- 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
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