Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours1,2,3. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells4. Here we show that mTOR (mammalian target of rapamycin5, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007)
Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008)
Klebanoff, C. A., Gattinoni, L. & Restifo, N. P. CD8+ T-cell memory in tumor immunology and immunotherapy. Immunol. Rev. 211, 214–224 (2006)
Seder, R. A., Darrah, P. A. & Roederer, M. T-cell quality in memory and protection: implications for vaccine design. Nature Rev. Immunol. 8, 247–258 (2008)
Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006)
Cao, W. et al. Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nature Immunol. 9, 1157–1164 (2008)
Sinclair, L. V. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nature Immunol. 9, 513–521 (2008)
Sauer, S. et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl Acad. Sci. USA 105, 7797–7802 (2008)
Haxhinasto, S., Mathis, D. & Benoist, C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565–574 (2008)
Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4, 1191–1198 (2003)
Huster, K. M. et al. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc. Natl Acad. Sci. USA 101, 5610–5615 (2004)
Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrançois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo . Nature Immunol. 1, 426–432 (2000)
Tan, J. T. et al. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med. 195, 1523–1532 (2002)
Wherry, E. J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nature Immunol. 4, 225–234 (2003)
Sarkar, S. et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 205, 625–640 (2008)
Joshi, N. S. et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007)
Grayson, J. M., Zajac, A. J., Altman, J. D. & Ahmed, R. Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. J. Immunol. 164, 3950–3954 (2000)
Storni, T. et al. Nonmethylated CG motifs packaged into virus-like particles induce protective cytotoxic T cell responses in the absence of systemic side effects. J. Immunol. 172, 1777–1785 (2004)
Ohtani, M. et al. Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. Blood 112, 635–643 (2008)
Weichhart, T. et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29, 565–577 (2008)
Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002)
Kim, D. H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002)
Kaech, S. M. & Wherry, E. J. Heterogeneity and cell-fate decisions in effector and memory CD8(+) T cell differentiation during viral infection. Immunity 27, 393–405 (2007)
Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998)
We thank B. T. Konieczny for technical assistance; D. Garber for providing us with the MVA; R. Amara for help developing rhesus macaque assays; W. Hahn for providing pMKO.1 GFP vector; and E. Strobert and P. L. Turner for technical assistance. This work was supported by NIH grants AI030048 (to R.A.) and N01-AI-50025 and AI040519 (to C.P.L).
Author Contributions K.A. and R.A. designed mouse experiments; A.P.T., V.O.S., S.G. and C.P.L designed macaque experiments; K.A. performed mouse experiments; A.P.T., V.O.S. and S.G. performed macaque experiments; K.A. and R.A. analysed mouse data; K.A., A.P.T., V.O.S., S.G. and C.P.L analysed macaque data; S.A.K. and M.F.B. provided critical reagents; and K.A. and R.A. wrote the paper.
About this article
Cite this article
Araki, K., Turner, A., Shaffer, V. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009) doi:10.1038/nature08155
Pharmacological Research (2019)
Antileishmanial effect of rapamycin as an alternative approach to control Leishmania tropica infection
Veterinary Parasitology (2019)
Anti-Cancer Agents in Medicinal Chemistry (2019)
Journal for ImmunoTherapy of Cancer (2019)
Proceedings of the National Academy of Sciences (2019)