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

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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

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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.

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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

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

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