Regulation and function of mTOR signalling in T cell fate decisions
Open accessAbstract
The evolutionarily conserved kinase mTOR (mammalian target of rapamycin) couples cell growth and metabolism to environmental inputs in eukaryotes. T cells depend on mTOR signalling to integrate immune signals and metabolic cues for their proper maintenance and activation. Under steady-state conditions, mTOR is actively controlled by multiple inhibitory mechanisms, and this enforces normal T cell homeostasis. Antigen recognition by naive CD4(+) and CD8(+) T cells triggers mTOR activation, which in turn programmes the differentiation of these cells into functionally distinct lineages. This Review focuses on the signalling mechanisms of mTOR in T cell homeostatic and functional fates, and discusses the therapeutic implications of targeting mTOR in T cells.
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PI3K-AKT-mTOR signalling is essential for T cell activation and differentiation by upregulating metabolic programs and supporting their bioenergetic needs.
“It is well established that PI3K–AKT–mTOR signalling is essential for T cell activation and differentiation by upregulating metabolic programs and supporting their bioenergetic needs46,47.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [46]
In “Metabolism in T cell activation and differentiation” (page unavailable), the paper identifies PI3K–AKT as a central regulator of activation-induced metabolic reprogramming and says mTOR has a vital role in T-cell metabolic programmes. But “Sensing and propagating metabolic cues” (page unavailable) says the extent to which mTOR-dependent metabolism regulates differentiation remains contentious. The claim overstates that metabolic route as an established, essential basis for differentiation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRapamycin inhibition of mTOR boosts CD8+ T cell responses in preclinical studies.
“inhibition of mTOR, a PI3K pathway intermediate, with rapamycin has been shown to stimulate CD8 + T cell responses in preclinical studies (110).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [110]
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Insulin Signaling in Arthritis
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Bortezomib Sustains T Cell Function by Inducing miR-155-Mediated Downregulation of SOCS1 and SHIP1
Renrick, A. N., Thounaojam, M. C., de Aquino, M. T. P., Chaudhuri, E., Pandhare, J., Dash, C., & Shanker, A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.607044 · Cited by 43 · see citing works
Akhtar, A., Shakir, M., Ansari, M. S., Divya, Faizan, M. I., Chauhan, V., Singh, A., Alam, R., Azmi, I., Sharma, S., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102021 · Cited by 21 · see citing works
Fritsch, P., Craddock, T. J., del Rosario, R. M., Rice, M. A., Smylie, A., Folcik, V. A., de Vries, G., Fletcher, M. A., Klimas, N. G., & Broderick, G. (2013) · Systems Biomedicine · doi:10.4161/sysb.28948 · Cited by 16 · see citing works
- Authors
- Chi, H.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Chi, Hongbo
- ORCID
- Chi, Hongbo
- Venue
- Nature Reviews Immunology
- Published
- 2012-04-20
- Volume
- 12
- Issue
- 5
- Pages
- 325-338
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- PMC
- PMC3417069
- OpenAlex
- W2063888187
- Cited by
- 1,035
- References
- 154
- Citations by year
- 2026: 70 · 2025: 89 · 2024: 90 · 2023: 103 · 2022: 96 · 2021: 94 · 2020: 82 · 2019: 51 · 2018: 62 · 2017: 77 · 2016: 60 · 2015: 57 · 2014: 39 · 2013: 49 · 2012: 16
- FWCI
- 4.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research Institute
- National Multiple Sclerosis Society
- Lupus Research Institute
- Lupus Research Alliance
- American Lebanese Syrian Associated Charities
- Multiple Sclerosis Society
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R21AI094089)
- National Institute of Neurological Disorders and Stroke (R01NS064599)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR053573)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- mTOR signaling, T cell fate determination, T cell homeostasis, T cell activation, T cell metabolism, T cell differentiation, CD4+ T cells, CD8+ T cells, mTOR inhibitors, immune checkpoint therapy, antigen recognition
- MeSH terms
- Animals, Humans, T-Lymphocytes, Signal Transduction, Cell Lineage, TOR Serine-Threonine Kinases
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