Cited by 274T-cell and B-cell ImmunologyPI3K/AKT/mTOR signaling in cancerSignaling Pathways in Disease

The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

Zheng, Yan, Collins, Samuel L, Lutz, Michael A, Allen, Amy N, Kole, Thomas P, Zarek, Paul E, Powell, Jonathan D·2007·The Journal of Immunology

DOI 10.4049/jimmunol.178.4.2163

Open this paper in CoChat — free account

Abstract

Whether TCR engagement leads to activation or tolerance is determined by the concomitant delivery of multiple accessory signals, cytokines, and environmental cues. In this study, we demonstrate that the mammalian target of rapamycin (mTOR) integrates these signals and determines the outcome of TCR engagement with regard to activation or anergy. In vitro, Ag recognition in the setting of mTOR activation leads to full immune responses, whereas recognition in the setting of mTOR inhibition results in anergy. Full T cell activation is associated with an increase in the phosphorylation of the downstream mTOR target S6 kinase 1 at Thr(421)/Ser(424) and an increase in the mTOR-dependent cell surface expression of transferrin receptor (CD71). Alternatively, the induction of anergy results in markedly less S6 kinase 1 Thr(421)/Ser(424) phosphorylation and CD71 surface expression. Likewise, the reversal of anergy is associated not with proliferation, but rather the specific activation of mTOR. Importantly, T cells engineered to express a rapamycin-resistant mTOR construct are resistant to anergy induction caused by rapamycin. In vivo, mTOR inhibition promotes T cell anergy under conditions that would normally induce priming. Furthermore, by examining CD71 surface expression, we are able to distinguish and differentially isolate anergic and activated T cells in vivo. Overall, our data suggest that by integrating environmental cues, mTOR plays a central role in determining the outcome of Ag recognition.

Integrity signals

Registry

Crossref · 10.4049/jimmunol.178.4.2163

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
mTOR Interacts with Raptor to Form a Nutrient-Sensitive Complex that Signals to the Cell Growth Machinery
Kim, D., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R., Erdjument‐Bromage, H., Tempst, P., & Sabatini, D. M. (2002) · Cell · doi:10.1016/s0092-8674(02)00808-5 · Cited by 3,051
Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways
Larsen, C. P., Elwood, E. T., Alexander, D. Z., Ritchie, S. C., Hendrix, R. C., Tucker‐Burden, C., Cho, H. R., Aruffo, A. A., Hollenbaugh, D. L., Linsley, P. S., et al. (1996) · Nature · doi:10.1038/381434a0 · Cited by 1,455
Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy.
Schwartz, R. H. (1992) · Cell · doi:10.1016/s0092-8674(05)80055-8 · Cited by 1,293
Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases
Chung, J., Kuo, C. J., Crabtree, G. R., & Blenis, J. (1992) · Cell · doi:10.1016/0092-8674(92)90643-q · Cited by 1,151
GβL, a Positive Regulator of the Rapamycin-Sensitive Pathway Required for the Nutrient-Sensitive Interaction between Raptor and mTOR
Kim, D., Sarbassov, D. D., Ali, S. M., Latek, R. R., Guntur, K., Erdjument‐Bromage, H., Tempst, P., & Sabatini, D. M. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00114-x · Cited by 992
Akt Maintains Cell Size and Survival by Increasing mTOR-dependent Nutrient Uptake
Edinger, A. L., & Thompson, C. B. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.01-12-0584 · Cited by 592
Identification of an 11-kDa FKBP12-rapamycin-binding domain within the 289-kDa FKBP12-rapamycin-associated protein and characterization of a critical serine residue.
Chen, J., Zheng, X. F., Brown, E. J., & Schreiber, S. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.11.4947 · Cited by 556
Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein.
Peterson, R., Desai, B. N., Hardwick, J. S., & Schreiber, S. (1999) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.96.8.4438 · Cited by 496
IL-7 Enhances the Survival and Maintains the Size of Naive T Cells
Rathmell, J. C., Farkash, E. A., Gao, W., & Thompson, C. B. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.12.6869 · Cited by 459
Prevention of T Cell Anergy by Signaling Through the γ c Chain of the IL-2 Receptor
Boussiotis, V. A., Barber, D. L., Nakarai, T., Freeman, G. J., Gribben, J. G., Bernstein, G. M., D’Andrea, A. D., Ritz, J., & Nadler, L. M. (1994) · Science · doi:10.1126/science.7973657 · Cited by 307
The CD28 and CTLA-4 Receptors Associate with the Serine/Threonine Phosphatase PP2A
Chuang, E., Fisher, T. S., Morgan, R. W., Robbins, M. D., Duerr, J. M., Vander Heiden, M. G., Gardner, J. P., Hambor, J. E., Neveu, M. J., & Thompson, C. B. (2000) · Immunity · doi:10.1016/s1074-7613(00)00031-5 · Cited by 303 · cited 1×
“Of interest, protein phosphatase 2A has been shown to associate with CD28 and CTLA-4 and negatively regulate T cell activation (34).”
Background
Inhibition of Cell Cycle Progression by Rapamycin Induces T Cell Clonal Anergy Even in the Presence of Costimulation
Powell, J. D., Lerner, C. G., & Schwartz, R. H. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.5.2775 · Cited by 290
Activation of PI3K Is Indispensable for Interleukin 7–mediated Viability, Proliferation, Glucose Use, and Growth of T Cell Acute Lymphoblastic Leukemia Cells
Barata, J. T., da Silva, A. B. G., Brandão, J. G., Nadler, L. M., Cardoso, A. A., & Boussiotis, V. A. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040789 · Cited by 289
mTOR integrates amino acid- and energy-sensing pathways
Tokunaga, C., Yoshino, K., & Yonezawa, K. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.07.019 · Cited by 277
TOR Signaling
Harris, T. E., & Lawrence, J. C. (2003) · Science s STKE · doi:10.1126/stke.2122003re15 · Cited by 239
p27kip1 functions as an anergy factor inhibiting interleukin 2 transcription and clonal expansion of alloreactive human and mouse helper T lymphocytes
Boussiotis, V. A., Freeman, G. J., Taylor, P. A., Berezovskaya, A., Grass, I., Blazar, B. R., & Nadler, L. M. (2000) · Nature Medicine · doi:10.1038/73144 · Cited by 231
Distinct Signaling Events Downstream of mTOR Cooperate To Mediate the Effects of Amino Acids and Insulin on Initiation Factor 4E-Binding Proteins
Wang, X., Beugnet, A., Murakami, M., Yamanaka, S., & Proud, C. G. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2558-2572.2005 · Cited by 207
Distinct Roles of the Phosphatidylinositol 3-Kinase and STAT5 Pathways in IL-7-Mediated Development of Human Thymocyte Precursors
Pallard, C., Stegmann, A. P. A., van Kleffens, T., Smart, F. M., Venkitaraman, A. R., & Spits, H. (1999) · Immunity · doi:10.1016/s1074-7613(00)80052-7 · Cited by 203
Use of adoptive transfer of T‐cell antigen‐receptor‐transgenic T cells for the study of T‐cell activation in vivo
Pape, K. A., Kearney, E. R., Khoruts, A., Mondino, A., Merica, R. R., Chen, Z., Ingulli, E. G., White, J., Johnson, J. G., & Jenkins, M. K. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb00959.x · Cited by 201
Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling
Brown, V. I., Fang, J.-J., Alcorn, K., Barr, R., Kim, J. M., Wasserman, R., & Grupp, S. (2003) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2436348100 · Cited by 168
Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone
Strömberg, T., Dimberg, A., Hammarberg, A., Carlson, K. E., Österborg, A., Nilsson, K., & Jernberg‐Wiklund, H. (2003) · Blood · doi:10.1182/blood-2003-05-1543 · Cited by 154
Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin
Colombetti, S., Basso, V., Mueller, D. L., & Mondino, A. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.5.2730 · Cited by 138
T Cell Effector Function and Anergy Avoidance Are Quantitatively Linked to Cell Division
Wells, A. D., Walsh, M. C., Sankaran, D., & Turka, L. A. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.5.2432 · Cited by 96
Antagonistic Roles for CTLA-4 and the Mammalian Target of Rapamycin in the Regulation of Clonal Anergy: Enhanced Cell Cycle Progression Promotes Recall Antigen Responsiveness
Vanasek, T. L., Khoruts, A., Zell, T., & Mueller, D. L. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.10.5636 · Cited by 79
Th1 cell anergy and blockade in G1a phase of the cell cycle.
Gilbert, K. M., & Weigle, W. O. (1993) · The Journal of Immunology · doi:10.4049/jimmunol.151.3.1245 · Cited by 72
Clonal Anergy Is Maintained Independently of T Cell Proliferation1
Colombetti, S., Benigni, F., Basso, V., & Mondino, A. (2002) · Journal of Immunology · doi:10.4049/jimmunol.169.11.6178 · Cited by 57
Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms
Masao, I. (2005) · Frontiers in bioscience · doi:10.2741/1742 · Cited by 55
Opposing Roles for the Cyclin-Dependent Kinase Inhibitor p27 kip1 in the Control of CD4+ T Cell Proliferation and Effector Function
Rowell, E. A., Walsh, M. C., & Wells, A. D. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.6.3359 · Cited by 53
Induction of Anergy in Th1 Cells Associated with Increased Levels of Cyclin-Dependent Kinase Inhibitors p21Cip1 and p27Kip1 1
Jackson, S. K., DeLoose, A., & Gilbert, K. M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.2.952 · Cited by 49
The Novel Cyclophilin Binding Compound, Sanglifehrin A, Disassociates G1 Cell Cycle Arrest from Tolerance Induction
Allen, A. N., Zheng, Y., Gardner, L. B., Safford, M., Horton, M. R., & Powell, J. D. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.8.4797 · Cited by 46
Novel Regulatory Mechanisms of mTOR Signaling
Chen, J. (2004) · Current topics in microbiology and immunology · doi:10.1007/978-3-642-18930-2_14 · Cited by 34
Low-Dose Radiation Plus Rapamycin Promotes Long-Term Bone Marrow Chimerism
Powell, J. D., Fitzhugh, C. D., Kang, E. M., Hsieh, M., Schwartz, R. H., & Tisdale, J. F. (2005) · Transplantation · doi:10.1097/01.tp.0000185299.72295.90 · Cited by 32
Expression of cell surface transferrin receptor and intracellular ferritin after in vitro stimulation of peripheral blood T lymphocytes
Pattanapanyasat, K., & Hoy, T. G. (1991) · European Journal Of Haematology · doi:10.1111/j.1600-0609.1991.tb00137.x · Cited by 28
DETERMINATION OF AN IMPROVED SIROLIMUS (RAPAMYCIN)-BASED REGIMEN FOR INDUCTION OF ALLOGRAFT TOLERANCE IN MICE TREATED WITH ANTILYMPHOCYTE SERUM AND DONOR-SPECIFIC BONE MARROW1
Hale, D. A., Gottschalk, R., Maki, T., & Monaco, A. P. (1998) · Transplantation · doi:10.1097/00007890-199802270-00004 · Cited by 27
The cyclin‐dependent kinase inhibitors p27Kip1 and p21Cip1 are not essential in T cell anergy
Verdoodt, B., Blazek, T., Rauch, P., Schuler, G., Steinkasserer, A., Lutz, M. B., & Funk, J. O. (2003) · European Journal of Immunology · doi:10.1002/eji.200323960 · Cited by 16
Untitled work
(2001) · doi:10.1002/1521-4141(200112)31:12

Flagged first, then by citations

Research works printed but not linked: 37

1992, Cell, 1065
2004, Genes Dev., 1926
2004, Biochem. Biophys. Res. Commun., 443
2004, Curr. Top. Microbiol. Immunol., 245
2003, Sci. STKE, re15
1999, J. Immunol., 2775
2001, J. Immunol., 5636
1993, J. Immunol., 1245
2001, Eur. J. Immunol., 3737
2000, Nat. Med., 290
2000, J. Immunol., 2432
2002, J. Immunol., 6178
2004, J. Immunol., 4797
2001, J. Immunol., 952
2006, J. Immunol., 2730
1992, Cell, 1227
2002, Cell, 163
2003, Mol. Cell, 895
2004, Blood, 3138
1994, Science, 1039
2001, J. Immunol., 6869
1999, Immunity, 525
2004, J. Exp. Med., 659
2003, Proc. Natl. Acad. Sci. USA, 15113
2002, Mol. Biol. Cell, 2276
1991, Eur. J. Haematol., 140
1995, Proc. Natl. Acad. Sci. USA, 4947
1997, Immunol. Rev., 67
2005, J. Immunol., 3359
2003, Eur. J. Immunol., 3154
2005, Front. Biosci., 2856
2005, Mol. Cell. Biol., 2558
1999, Proc. Natl. Acad. Sci. USA, 4438
2000, Immunity, 313
1996, Nature, 434
1998, Transplantation, 473
2005, Transplantation, 1541

Sorted by citations

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
SUnSET, a nonradioactive method to monitor protein synthesis
Schmidt, E. K., Clavarino, G., Ceppi, M., & Pierre, P. (2009) · Nature Methods · doi:10.1038/nmeth.1314 · Cited by 1,706
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
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
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 all 274

Authors: Zheng, Y., Collins, S. L., Lutz, M. A., Allen, A. N., Kole, T. P., Zarek, P. E., & Powell, J. D.
Affiliations: Johns Hopkins University (US)
ORCID: Zheng, Yan
Collins, Samuel L
Allen, Amy N
Powell, Jonathan D
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2007-02
Volume: 178
Issue: 4
Pages: 2163-2170
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.178.4.2163
OpenAlex: W1944331591
Cited by: 274
References: 37
Citations by year: 2026: 2 · 2025: 5 · 2024: 5 · 2023: 14 · 2022: 18 · 2021: 12 · 2020: 12 · 2019: 15 · 2018: 20 · 2017: 18 · 2016: 14 · 2015: 18 · 2014: 23 · 2013: 21 · 2012: 18
FWCI: 5.71
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: Johns Hopkins University
National Institutes of Health (1k22ai001773-01)
National Cancer Institute (R01CA098109, R01CA98109)
National Institute of Allergy and Infectious Diseases (5K22AI1773)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: mTOR, T cell anergy, T cell activation, T cell receptor signaling, transferrin receptor, rapamycin resistance, T cell tolerance, antigen recognition, T cell proliferation
MeSH terms: Animals, Gene Expression Regulation, Humans, Immunosuppressive Agents, Lymphocyte Activation, Protein Kinases, Receptors, Transferrin, T-Lymphocytes, Antigens, CD, Clonal Anergy, Antigen Presentation, Jurkat Cells, Ribosomal Protein S6 Kinases, Sirolimus, 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

A Role for Mammalian Target of Rapamycin in Regulating T Cell Activation versus Anergy

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks