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  • Review Article
  • Published:

Immunoregulatory functions of mTOR inhibition

Nature Reviews Immunology volume 9, pages 324–337 (2009)Cite this article

Key Points

  • The atypical serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. A complex formed between the immunosuppressive drug rapamycin and the immunophilin FK506-binding protein 1A, 12 kDA (FKBP12) inhibits mTOR kinase activity.

  • mTOR functions in at least two multi-protein complexes: mTOR complex 1 (mTORC1) and mTORC2. mTOR in mTORC1 is highly sensitive to inhibition by rapamycin, whereas mTOR in mTORC2 is resistant to rapamycin. mTORC1 regulates cell growth downstream of phosphoinositide 3-kinase–AKT signalling, in which active mTORC1 phosphorylates S6 kinase (S6K1) and the eukaryotic translation initiation factor-binding protein 1 (EIF4EBP1). Both of these activities promote mRNA translation and cell growth.

  • Rapamycin exerts many effects on the differentiation and function of professional antigen-presenting cells (APCs). mTOR inhibition by rapamycin impedes antigen uptake and can modulate antigen presentation by dendritic cells (DCs); its differential effects on cytokine production and chemokine receptor expression by DCs regulate interactions between innate and adaptive immune cells.

  • Recent findings have shed light on previously unappreciated effects of mTOR inhibition on T cells. Rapamycin induces thymic involution, whereas the ontogeny of naturally occurring regulatory T (TReg) cells seems to be less affected. During conventional T cell activation, rapamycin-mediated mTOR inhibition blocks cell cycle progression and can sequester activated T cells in secondary lymphoid tissues. By contrast, rapamycin causes an increase in the frequency of FOXP3 (forkhead box P3)+ T cells, reflecting both the ability of TReg cells to proliferate in the presence of rapamycin and the promotion of FOXP3 expression in peripheral T cells that are then converted into modulators of immune reactivity.

  • mTOR inhibition is a promising therapeutic strategy to prevent rejection in transplantation and for autoimmune disease. Differential effects of rapamycin on T cells and TReg cells (both naturally occurring and inducible) favour its ability to promote tolerance in tolerance-enhancing protocols. In addition, adoptively transferred rapamycin-conditioned APCs inhibit organ allograft rejection and graft-versus-host disease following haematopoietic cell transplantation.

  • Ongoing and future areas of enquiry, which could prove fruitful, include distinguishing the role of mTORC1 and mTORC2 in the regulation of immune responses and tolerance, investigating the role of the mTOR–survivin–aurora B complex in T cell activation and ascertaining the mechanisms that determine TReg cell resistance to rapamycin and mTOR-mediated regulation of FOXP3 expression, as well as their relevance to therapy.

Abstract

The potent immunosuppressive action of rapamycin is commonly ascribed to inhibition of growth factor-induced T cell proliferation. However, it is now evident that the serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. mTOR regulates diverse functions of professional antigen-presenting cells, such as dendritic cells (DCs), and has important roles in the activation of effector T cells and the function and proliferation of regulatory T cells. In this Review, we discuss our current understanding of the mTOR pathway and the consequences of mTOR inhibition, both in DCs and T cells, including new data on the regulation of forkhead box P3 expression.

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Figure 1: mTORC1 and mTORC2 signalling pathways.
Figure 2: mTOR and rapamycin regulate APC function.
Figure 3: Proposed molecular mechanisms responsible for T cell susceptibility or resistance to rapamycin.
Figure 4: Mechanisms of FOXP3 induction in naive T cells.

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Acknowledgements

The authors' work is supported by National Institutes of Health (NIH) grants R01 AI060994, R01 AI067541 and U01 AI051698 and by the Roche Organ Transplantation Research Foundation 874,279,717 (to A.W.T.), by an American Heart Association Beginning Grant-in-Aid (to G.R.) and by NIH postdoctoral fellowship F32 AI072940 (to H.R.T.)

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  1. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, 15261, Pennsylvania, USA

    Angus W. Thomson, Hēth R. Turnquist & Giorgio Raimondi

  2. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, 15261, Pennsylvania, USA

    Angus W. Thomson

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Glossary

Graft-versus-host disease

(GVHD). A disease that results from immunological attack by donor allogeneic T cells transferred with the allograft (such as bone marrow, liver or gut) of target recipient organs or tissues (such as skin or gut). GVHD occurs in graft recipients who cannot eliminate the host-reactive donor T cells owing to immunosuppression, immunological immaturity or tolerance of the recipient.

Immunophilin

A peptidyl-prolyl isomerase that is targeted by certain immunosuppressive drugs (such as cyclosporin A, FK506 and rapamycin). The drug–immunophilin complex is responsible for the immunosuppressive action of the drug.

Autophagy

A tightly regulated catabolic process that involves degradation of the cell's own intracellular components through the lysosomal machinery and is a normal part of cell growth, development and homeostasis.

Small interfering RNA

A class of 20–25-nucleotide long double-stranded RNA molecules that are involved in the RNA interference pathway, which interferes with the expression of a specific gene. Also known as silencing RNA.

FMS-like tyrosine kinase 3 ligand

(FLT3L). An endogenous cytokine that stimulates stem cell and progenitor cell proliferation through binding to the FLT3 receptor (a type III receptor tyrosine kinase member of the platelet-derived growth factor family). FLT3L administration markedly increases dendritic cell numbers in lymphoid and non-lymphoid tissues.

Macropinocytosis

Invagination of the cell membrane to form a pocket that pinches off into the cell to form a vesicle filled with extracellular fluid and the molecules within it. The vesicle travels into the cytoplasm and fuses with other vesicles, such as lysosomes and endosomes.

Calcineurin inhibitor

A complex of either cyclosporin A and cyclophilin, or FK506 and FKBP12, that inhibits the phosphatase activity of calcineurin.

Minor histocompatibility antigen

An antigenic peptide derived from polymorphic cellular proteins (alloantigens) bound to MHC class I molecules that can cause rejection of MHC-matched grafts.

Aggresome

A proteinaceous inclusion body that forms (within dendritic cells and other cells) when the cell's degradation machinery is impaired or overwhelmed under stress and that sequesters potentially toxic aggregates for subsequent clearance. Dendritic cell aggresome-like structures are known as DALIS.

Two-signal T cell activation model

The concept that both the peptide–MHC complex (signal 1) and the co-stimulatory signals that are delivered by CD80 and CD86 expressed by antigen-presenting cells (signal 2) are required for T cell activation. Absence of signal 2 results in the induction of T cell anergy or deletion.

T cell anergy

A state of T cell unresponsiveness to stimulation with antigen. It can be induced by stimulation with a large amount of specific antigen in the absence of co-stimulatory molecule engagement.

T regulatory type 1 (TR1) cell

A subset of CD4+ regulatory T cells that secrete high levels of interleukin-10 (IL-10) and that downregulate T helper 1 (TH1) and (TH2) cell responses in vitro and in vivo through the secretion of soluble IL-10 and transforming growth factor-β.

IPEX

A rare human disease that is linked to dysfunction of the transcriptional factor forkhead box P3 (FOXP3) and that is characterized by the development of autoimmunity.

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Thomson, A., Turnquist, H. & Raimondi, G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 9, 324–337 (2009). https://doi.org/10.1038/nri2546

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