The Mammalian Target of Rapamycin: Linking T Cell Differentiation, Function, and Metabolism

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2010 Sep 28

PMID 20870173

Citations 269

Authors

Jonathan D Powell

Greg M Delgoffe

Affiliations

Soon will be listed here.

Abstract

In the two-signal model of T cell activation, the outcome of antigen recognition is determined by the integration of multiple cues in the immune microenvironment. mTOR is an evolutionarily conserved PI3-kinase family member that plays a central role in integrating environmental cues in the form of amino acids, energy, and growth factors. Recently, an increasingly important role for mTOR in directing T cell activation and differentiation has become apparent. Here we review recent findings demonstrating the ability of mTOR to interpret signals in the immune microenvironment and program the generation of CD4(+) effector versus regulatory T cells, the generation of CD8(+) effector versus memory cells, T cell trafficking, and T cell activation versus anergy. The key theme to emerge from these studies is that the central role of mTOR provides a direct link between T cell metabolism and function.

Citing Articles

The role of mTOR activation in steroid-resistant asthma: insights from particulate matter-induced mouse model and patient studies.

Park H, Lee S, Lee H Inflamm Res. 2025; 74(1):19.

PMID: 39812811 DOI: 10.1007/s00011-025-01992-y.

A comprehensive overview of tolerogenic vaccine adjuvants and their modes of action.

Arve-Butler S, Moorman C Front Immunol. 2025; 15:1494499.

PMID: 39759532 PMC: 11695319. DOI: 10.3389/fimmu.2024.1494499.

Engineering bacteria for cancer immunotherapy by inhibiting IDO activity and reprogramming CD8+ T cell response.

Wang H, Xu F, Yao C, Dai H, Xu J, Wu B Proc Natl Acad Sci U S A. 2024; 121(52):e2412070121.

PMID: 39693352 PMC: 11670085. DOI: 10.1073/pnas.2412070121.

Targeting metabolic dysfunction of CD8 T cells and natural killer cells in cancer.

Viel S, Vivier E, Walzer T, Marcais A Nat Rev Drug Discov. 2024; 24(3):190-208.

PMID: 39668206 DOI: 10.1038/s41573-024-01098-w.

Pathway of LCK Tyrosine Kinase and mTOR Signaling in Children with T-Cell Acute Lymphoblastic Leukemia.

Rocka A, Suchcicka M, Jankowska A, Wozniak M, Lejman M Appl Clin Genet. 2024; 17:187-198.

PMID: 39583285 PMC: 11585986. DOI: 10.2147/TACG.S494389.

References

Araki K, Turner A, Shaffer V, Gangappa S, Keller S, Bachmann M . mTOR regulates memory CD8 T-cell differentiation. Nature. 2009; 460(7251):108-12. PMC: 2710807. DOI: 10.1038/nature08155. View

Colombetti S, Benigni F, Basso V, Mondino A . Clonal anergy is maintained independently of T cell proliferation. J Immunol. 2002; 169(11):6178-86. DOI: 10.4049/jimmunol.169.11.6178. View

Dennis P, Fumagalli S, Thomas G . Target of rapamycin (TOR): balancing the opposing forces of protein synthesis and degradation. Curr Opin Genet Dev. 1999; 9(1):49-54. DOI: 10.1016/s0959-437x(99)80007-0. View

Powell J, Lerner C, Schwartz R . Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol. 1999; 162(5):2775-84. View

Basu S, Golovina T, Mikheeva T, June C, Riley J . Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol. 2008; 180(9):5794-8. PMC: 2504517. DOI: 10.4049/jimmunol.180.9.5794. View

Braun V, Pilsl H, Gross P . Colicins: structures, modes of action, transfer through membranes, and evolution. Arch Microbiol. 1994; 161(3):199-206. DOI: 10.1007/BF00248693. View

Proud C . Amino acids and mTOR signalling in anabolic function. Biochem Soc Trans. 2007; 35(Pt 5):1187-90. DOI: 10.1042/BST0351187. View

Sinclair L, Finlay D, Feijoo C, Cornish G, Gray A, Ager A . Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol. 2008; 9(5):513-21. PMC: 2857321. DOI: 10.1038/ni.1603. View

Manning B, Cantley L . Rheb fills a GAP between TSC and TOR. Trends Biochem Sci. 2003; 28(11):573-6. DOI: 10.1016/j.tibs.2003.09.003. View

10.

Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M . T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008; 105(22):7797-802. PMC: 2409380. DOI: 10.1073/pnas.0800928105. View

11.

Lafferty K, Cunningham A . A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975; 53(1):27-42. DOI: 10.1038/icb.1975.3. View

12.

Curtsinger J, Mescher M . Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol. 2010; 22(3):333-40. PMC: 2891062. DOI: 10.1016/j.coi.2010.02.013. View

13.

Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X . TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006; 126(5):955-68. DOI: 10.1016/j.cell.2006.06.055. View

14.

Stephenson L, Park D, Mora A, Goenka S, Boothby M . Sequence motifs in IL-4R alpha mediating cell-cycle progression of primary lymphocytes. J Immunol. 2005; 175(8):5178-85. DOI: 10.4049/jimmunol.175.8.5178. View

15.

Hidayat S, Yoshino K, Tokunaga C, Hara K, Matsuo M, Yonezawa K . Inhibition of amino acid-mTOR signaling by a leucine derivative induces G1 arrest in Jurkat cells. Biochem Biophys Res Commun. 2003; 301(2):417-23. DOI: 10.1016/s0006-291x(02)03052-8. View

16.

Foley J, Jung U, Miera A, Borenstein T, Mariotti J, Eckhaus M . Ex vivo rapamycin generates donor Th2 cells that potently inhibit graft-versus-host disease and graft-versus-tumor effects via an IL-4-dependent mechanism. J Immunol. 2005; 175(9):5732-43. DOI: 10.4049/jimmunol.175.9.5732. View

17.

Kopf H, de la Rosa G, Howard O, Chen X . Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Immunopharmacol. 2007; 7(13):1819-24. PMC: 2223142. DOI: 10.1016/j.intimp.2007.08.027. View

18.

Delgoffe G, Powell J . mTOR: taking cues from the immune microenvironment. Immunology. 2009; 127(4):459-65. PMC: 2729523. DOI: 10.1111/j.1365-2567.2009.03125.x. View

19.

Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside T . Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One. 2009; 4(6):e5994. PMC: 2694984. DOI: 10.1371/journal.pone.0005994. View

20.

Jones R, Thompson C . Revving the engine: signal transduction fuels T cell activation. Immunity. 2007; 27(2):173-8. DOI: 10.1016/j.immuni.2007.07.008. View