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Keywords:

  • Dendritic cell;
  • immunosuppression;
  • inflammation;
  • interferon;
  • rapamycin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

The mammalian target of rapamycin (mTOR) is an evolutionary conserved serine–threonine kinase that senses various environmental stimuli in most cells primarily to control cell growth. Restriction of cellular proliferation by mTOR inhibition led to the use of mTOR inhibitors as immunosuppressants in allogeneic transplantation as well as novel anticancer agents. However, distinct inflammatory side effects such as fever, pneumonitis, glomerulonephritis or anemia of chronic disease have been observed under this treatment regime. Apart from the mere cell-cycle regulatory effect of mTOR in dividing cells, recent data revealed a master regulatory role of mTOR in the innate immune system. Hence, inhibition of mTOR promotes proinflammatory cytokines such as IL-12 and IL-1β, inhibits the anti-inflammatory cytokine IL-10 and boosts MHC antigen presentation via autophagy in monocytes/macrophages and dendritic cells. Moreover, mTOR regulates type I interferon production and the expression of chemokine receptors and costimulatory molecules. These results place mTOR in a complex immunoregulatory context by controlling innate and adaptive immune responses. In this review, we discuss the clinical consequences of mTOR-inhibitor therapy and aim to integrate this recent data into our current view of the molecular mechanisms of clinically employed mTOR inhibitors and discuss their relevance with special emphasis to transplantation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

Over the past decade new immunosuppressive compounds with novel mechanisms of action have become available, thereby increasing the options for novel immuno-suppressive strategies and potentially allowing to reduce the side effects associated with calcineurin inhibitor (CNI) therapy. Inhibitors of the mammalian target of rapamycin (mTOR) including rapamycin (sirolimus) and RAD0001 (everolimus) belong to the newest agents and current clinical and experimental data have not only allowed to obtain information regarding their immunosuppressive potency and side effect profile, but also helped to get insight into their molecular mode of action.

mTOR inhibitors (mTOR-I) have been evaluated in several controlled trials and data from some thousands of renal transplant patients have been obtained (1,2). During the years, however, several distinct mTOR-I–associated side effects have been observed including nephrotoxicity, dyslipidemia, delayed wound healing and leucopenia (1,3). Conversion from a CNI to an mTOR-I in kidney transplant recipients has been found to be associated with a high discontinuation rate of up to 28% of patients mostly due to adverse effects (2). One particular observation in most trials of transplant patients as well as in patients treated with mTOR-I as anticancer agents was the emergence of distinct inflammatory diseases most prominently mTOR-I–associated pneumonitis, but also de novo glomerulonephritis, systemic inflammatory response syndrome (SIRS) and anemia of chronic disease (3–6). Provoked by these findings, we studied the putative role of mTOR in regulating inflammation along with several other basic research groups that also helped to establish a conspicuous role of mTOR in the innate immune cell compartment. Here we bring together this clinical and experimental data and aim to summarize the divergent functions of mTOR in innate immunity with particular emphasis to transplantation immunity.

Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

The introduction of rapamycin led to an increased frequency of unexplained interstitial pneumonitis in renal transplant patients (6), which was later also observed in liver and heart transplant patients (6). Recently, this inflammatory disorder was also reported in everolimus-treated nontransplanted metastatic renal cell carcinoma patients at a frequency of 8% (4). In renal transplant patients, the estimated frequency is between 5% and 11% (6). Clinically, pneumonitis presents like typical pneumonia with increased systemic inflammatory parameters, fever and cough, but unresponsive to antimicrobial therapy. Usually, mTOR-I–associated pneumonitis resolves after drug withdrawal (6). mTOR-I–associated pneumonitis is characterized histologically by predominant CD4-positive helper cells and neutrophils and may in later stages progress to organizing pneumonia (bronchiolitis obliterans organizing pneumonia). Patients under mTOR-I therapy may also present with fever of unknown origin or SIRS in the absence of typical infectious signs. Hence, in the CONVERT trial, which evaluated the safety and efficacy of conversion from CNI to sirolimus in 555 renal transplant patients, 20.5% of mTOR-I–converted patients had fever unrelated to infection compared to 9.4% of CNI-treated patients (7). Moreover, mTOR-I–treated patients may present with unusual inflammatory foci (e.g. chronic pyogenic periungual inflammation or purulent lymphocele) with or without evidence of a microbial involvement that rapidly disappear after drug withdrawal (6). Skin inflammation including skin rash and acne as typical mTOR-I side effect is reported to be about—three to four times higher in sirolimus-treated patients than in CNI patients (2,7).

As another potential inflammatory consequence of mTOR-I therapy, anemia of chronic disease has been described. In the above-mentioned CONVERT trial, anemia as treatment-emergent adverse event was reported in 36.3% of sirolimus-treated patients vs. 16.5% of CNI-treated patients (7). Thaunat et al. (5) analyzed stable renal transplant patients on CsA-based immunosuppression that were converted to sirolimus and demonstrated a significant decrease in mean hemoglobin along with microcytic aregenerative anemia with low serum iron despite high ferritinemia consistent with anemia of chronic inflammation. Interestingly, typical proinflammatory cytokines such as IL-6 and TNF-α were increased in anemic patients, while the anti-inflammatory cytokine IL-10 was suppressed after conversion to sirolimus (5). In all patients, the inflammatory effects along with the microcytic anemia were reversible after drug discontinuation.

A distinct nephrotoxic potential of mTOR-I has been described, because mTOR-I increase apoptosis of tubular cells and may also affect podocytes leading to a worsening of preexisting proteinuria potentially associated with focal segmental glomerular sclerosis (7). Moreover, mTOR-I–associated proinflammatory conditions within the renal parenchyma and the induction of glomerulonephritis have also been reported as several cases of glomerulonephritis in renal transplant recipients emerging after late conversion to sirolimus resulted in clinical remission after withdrawal of the mTOR-I and reintroduction of the CNI (8). De novo occurrence of necrotizing glomerulonephritis in a renal allograft patient after late conversion from a CNI to everolimus ameliorated after withdrawal of the mTOR-I. Putative proinflammatory effects of mTOR inhibition were also detected in experimental models of glomerulonephritis. In a mesangial proliferative glomerulonephritis model, everolimus promoted inflammatory glomerular damage (9). Similarly, in a remnant kidney model, everolimus worsened disease progression including glomerular inflammation, while others actually described a beneficial effect of mTOR-I in distinct models of renal injury. Similar discrepancies were observed by Hochegger et al. (10) in an anti-GBM glomerulonephritis model where late addition of sirolimus exacerbated glomerular inflammation, while early sirolimus therapy was protective. Such phenomena have also been explained by the strong suppressive effect of sirolimus on adaptive immune responses, which might prevail when administered prior to induction of the immune response while at later time points sirolimus might predominantly affect the effector phase of innate immune cells and cause inflammation. Collectively, a variety of inflammatory disorders have been observed both in transplanted and nontransplant patients treated with mTOR-I as well as in experimental models of inflammation. Although some of these disorders have been previously associated with infections, distinct clinical pictures unrelated to infectious stimuli including pneumonitis, anemia and fever have been recognized as a consequence of mTOR-I therapy.

The mTOR Signaling Pathway: Molecular Basics

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

The mTOR pathway is activated by a variety of different classes of stimuli: it senses cellular energy levels by monitoring the cellular ATP:AMP ratio, insulin, amino acids and signals from the Wnt family (11). Recent data from the innate immune system shows that mTOR is activated after stimulation by Toll-like receptors (TLRs) (Figure 1) (12–14). Following receptor engagement, phosphoinositide 3-kinase (PI3K) phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3) as second messenger to recruit and activate downstream targets including the kinase Akt. One main effector of Akt is the tuberous sclerosis complex (TSC) protein 2 (TSC2) (11). TSC2 is a tumor suppressor that forms a heterodimeric complex with TSC1. TSC2 is phosphorylated and inactivated by Akt and the TSC1–TSC2 complex negatively regulates the serine–threonine kinase mTOR. mTOR controls protein synthesis through the direct phosphorylation and inactivation of the repressor of mRNA translation, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and through phosphorylation and activation of S6 kinase (S6K1 or p70S6K), which in turn phosphorylates the ribosomal protein S6. Loss of mTOR function leads to an arrest in the G1 phase of the cell cycle along with a severe reduction in protein synthesis (11).

image

Figure 1. The mammalian target of rapamycin (mTOR) pathway in myeloid phagocytes. mTOR is found in two distinct protein complexes. mTOR complex 1 (mTORC1) (composed of mTOR, Raptor, mLST8) is rapamycin sensitive and is regulated by growth factors, Toll-like receptor (TLR) ligands and nutrients. By contrast, mTORC2 (composed of mTOR, Rictor, Sin1, mLST8) is not directly inhibited by rapamycin. Rapamycin directly binds FKBP12 and this complex inhibits mTORC1. TLR ligands trigger mTORC1 activity via PI3K that stimulates phosphatidylinositol-3,4,5-triphosphate (PIP3) production, which recruits Akt to the cell membrane. This finally results in the phosphorylation of its threonine 308 through the phosphoinositide-dependent kinase 1 (PDK1) and its serine 473 by the mTORC2 complex. Active Akt phosphorylates TSC2 and thereby relieves the inhibitory activity of the TSC1–TSC2 complex on mTORC1. Activation of mTORC1 limits the activity of the transcription factor NF-κB and its downstream genes such as IL-12, whereas mTORC1 stimulates activation of the signal transducer and activator of transcription 3 (STAT3) to promote expression of IL-10. Moreover, mTORC1 activates interferon-regulated factor (IRF)-5 and IRF-7 to enable the production of type I interferons (IFNs). In addition, mTORC1 negatively regulates caspase-1 activity to produce bioactive IL-1β.

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mTOR exists in two complexes in the cell. mTOR complex 1 (mTORC1) consists of Raptor, which recruits p70S6K and 4-E-BP1, and the adaptor protein mLST8 (11). Rapamycin forms a complex with FK506-binding protein 12 (FKBP12) and as a complex inhibits mTORC1 via blocking its interaction with Raptor. mTORC2 is composed of mTOR, mLST8 and the adaptor proteins Rictor and Sin1. mTORC2 is rapamycin-insensitive, regulates the actin cytoskeleton dynamics and controls phosphorylation of Akt Ser 473. Long-term treatment with rapamycin alters the mTORC1/C2 equilibrium resulting in reduced mTORC2 levels and impaired Akt signaling (15). Collectively, receptor engagement leads to a coordinated activation of PI3K, Akt and TSC1–TSC2, which are integrated at the level of mTORC1 (Figure 1).

The mTOR pathway in lymphoid and natural killer cells

In the adaptive immune system, stimulation of antigen receptors (T- and B-cell receptor) and various cytokine receptors (e.g. IL-2 receptor) lead to the activation of mTOR. mTOR controls cell cycle progression from G1 into S phase in cytokine-stimulated T cells. Hence, rapamycin potently decreases the proliferation of CD4+ T lymphocytes. Moreover, mTOR might direct the differentiation of Th1 cells by inducing the production of IFN-γ after IL-12 receptor activation on T cells (16). Moreover, it is now clear that rapamycin is able to enrich CD4+CD25+ regulatory T (Treg) cells in vitro and there is some recent evidence that the mTOR pathway restrains the development of Treg cells (17). Hence, there is currently great interest in generating high numbers of Treg cells ex vivo for therapeutic use through inhibition of the mTOR pathway.

In natural killer (NK) cells, rapamycin similarly blocks progression from G1 to S phase of the cell cycle (18). However, mTOR does not seem to influence NK cell cytotoxicity or interferon-γ (INF-γ) production (18).

Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

A growing body of evidence indicates that in myeloid phagocytes such as monocytes, macrophages and myeloid DC (mDC) the PI3K–mTOR pathway is crucially implicated in TLR signaling and serves as a possible decision maker to control the cellular response to pathogens by modulating cytokines, chemokines/chemokine receptors and type I IFN responses (Figure 1). Pharmacological or genetic disruption of PI3K results in excessive production of the Th1-promoting proinflammatory cytokine IL-12 in isolated murine splenic DCs (19). Overproduction of this cytokine in Leishmania major-infected PI3K p85−/− mice leads to a healing phenotype. Moreover, pharmacological inhibition of PI3K in a murine polymicrobial sepsis model increases mortality caused by an amplified production of proinflammatory cytokines including IL-1β, IL-6, IL-12 and TNF-α (17).

Several previous reports found an inhibitory effect of rapamycin on in vitro-generated DCs (20), whereas others did not observe any effect of mTOR inhibition on CD40L-simulated DC. However, the use of freshly isolated, unaltered human monocytes and primary human mDCs allowed to better analyze the impact of the TSC–mTOR pathway downstream of PI3K with regard to regulation of inflammatory responsiveness after TLR stimulation. Accordingly, inhibition of mTOR promotes IL-12p40/p70, IL-23, TNF-α and IL-6 production and protects mice against a lethal Listeria monocytogenes infection (14). Also in other studies, inhibition of mTOR enhances IL-12 and IL-23 in human and murine macrophages upon stimulation with diverse ligands including LPS and Mycobacterium tuberculosis, while production of IL-10 is blocked (Figure 1) (13,21,22). It is unclear at present why human in vitro-generated DCs behave differently than freshly isolated peripheral mDCs upon mTOR inhibition. One possible explanation for these seemingly anti-inflammatory effects of rapamycin is the fact that in vitro-generated DCs are differentiating and finally maturating for a period for up to 7 days in the presence of rapamycin and mTOR inhibition for such a prolonged period of time could lead to a suppression of vital nutritional functions of treated cells. In addition, these cells increase the expression of the negative TLR-signaling molecule ST2L, which might also explain their immunosuppressive phenotype (23). At the molecular level, the negative regulatory function of mTOR in myeloid cells and hence the proinflammatory action of mTOR-I is mediated by the transcription factors NF-κB and signal transducer and activator of transcription 3 (STAT3) (14). Inhibition of mTOR enhances inflammatory cytokine production via increased NF-κB activity but blocks the release of IL-10 via inactivated STAT3 in human monocytes. Of note, increased production of IL-12p40 after mTOR inhibition is not mediated by a lack of IL-10, but rather directly via increased NF-κB activity (14). Interestingly, inactivation of mTOR increases the lethality of endotoxin-mediated shock in mice, which correlates with enhanced levels of IL-1β. Indeed, mTOR suppresses caspase-1 activation and inhibits the release of bioactive IL-1β (13). Moreover, the mTOR pathway is important for the regulation of type I IFN production in murine DCs (Figure 1) but also in plasmacytoid DCs (12,13). Altogether, these data support a pivotal role of the PI3K–mTOR pathway in regulating inflammatory mediators in myeloid cells.

In line with the above conclusions, inhibition of mTOR in monocytes or DCs during the context of TLR stimulation enhances their T-cell–stimulatory capacity (14,21,24). Moreover, mTOR-inhibited APCs enhance the production of IFN-γ and IL-17 of T cells during a mixed lymphocyte reaction (MLR) (14,21). These results suggest that in vivo mTOR has also the potential to affect T-cell polarization by negatively regulating the priming of Th1- and Th17-T cells in myeloid immune cells. These effects have to be opposed to the potency of rapamycin to block IL-12 receptor-mediated activation of IFN-γ in T cells and therefore blocking of a Th1-dominated response.

MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

Autophagy is a catabolic process that degrades endogenous cellular components by transfer into lytic vacuolar compartments. It plays a role in cell growth, development and homeostasis to maintain a balance between the synthesis, degradation and subsequent recycling of cellular products (25). Autophagy has been shown to be essential to both innate and adaptive immunity by eliminating intracellular bacteria and viruses (25). mTOR is a critical negative regulator of autophagy and hence, mTOR-I induce autophagy (25). Interestingly, it has been shown that autophagy facilitates the presentation of endogenous proteins on MHC classes I and II molecules, thereby leading to activation of CD4+ T cells and connecting autophagy in innate immune cells with enhanced adaptive immunity. For example, in Mycobacterium tuberculosis-infected DCs, rapamycin-induced autophagy enhances the presentation of mycobacterial antigens (24). Stunningly, mice immunized with rapamycin-treated DCs, which were infected with the tuberculosis-vaccine strain BCG, show enhanced Th1-mediated protection when challenged with virulent Mycobacterium tuberculosis (24). These results show that mTOR inhibition in innate immune cells does not only enhance adaptive immune responses via augmented proinflammatory cytokine production and increased expression of costimulatory molecules but also via enhanced MHC antigen presentation by autophagy (Figure 1) (14,24). Therefore, induction of autophagy in innate immune cells via mTOR-I might interfere with potent immunosuppression. Indeed, recent evidence suggests that autophagy may be linked with graft dysfunction in experimental animal models of transplantation (26).

mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

Ischemia and reperfusion injury (IRI) is the main etiology of acute renal failure in transplanted kidneys and represents an inflammatory disease (27). Reperfusion of the microvasculature involves the activation of both neutrophils and macrophages. The recruitment of these leukocytes from the blood into the ischemic tissue follows a regulated multistep sequence involving distinct surface molecules. After chemotactic activation, firm leukocyte adherence to the endothelium through endothelial intercellular adhesion molecule (ICAM)-1 and leukocytic CD11b/CD18 represents the prerequisite for transendothelial migration. Moreover, higher levels of plasma ICAM-1 have been associated with primary graft dysfunction following human lung transplantation (28). Interestingly, rapamycin induces renal dysfunction after IRI in experimental models primarily thought to be mediated via exaggerated tubular cell apoptosis (27). However, rapamycin also potentiates thrombin-induced ICAM-1 expression by accelerating and stabilizing NF-κB activation in endothelial cells (29). These results indicate that mTOR negatively regulates ICAM-1 expression in endothelial cells to limit tissue infiltration of leukocytes.

Conclusion and Perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References

Although mTOR inhibition is exploited in many immunosuppressive protocols, the actual immunological consequences of rapamycin therapy are still incompletely defined in vivo. Although mTOR deficiency is embryonic lethal demonstrating that mTOR is crucial during development, mTOR inhibition has been demonstrated to result in distinct complications in patients. Because mTOR negatively regulates proinflammatory responses in monocytes and mDCs and also leads to enhanced leukocyte recruitment via ICAM-1 under mTOR inhibition in endothelial cells, it may be speculated that the clinically observed inflammatory side effects might be potentiated upon mTOR inhibition. Recent studies have revealed that mTOR holds a key position in the innate immune system (Table 1). Although mTOR physiologically limits inflammatory responses in myeloid cells such as monocytes/macrophages and DCs via modulation of classical transcription factors such as NF-κB and STAT3, it fosters type I IFN production in pDCs. These effects occur independent of the role of mTOR within the adaptive immune system, where primarily lymphocyte proliferation and also induction of Treg cells is controlled by mTOR (17). Thereby, the uniqueness of an immune response during mTOR inhibition is characterized by a potent suppression of CD4 effector T cells, promotion of Tregs and concomitantly an exaggerated activation of the innate arm of the immune system (Figure 2). The global result is suppression of diverse lymphocyte functions, but still innate immune cell activation that might occur in an unexpected manner and it is hypothesized that the genetic background of the host regulates the magnitude of this inflammatory reaction leading to the clinical emergence of inflammatory phenomena in a large fraction of mTOR-I–treated patients.

Table 1.  Overview of direct effects of mTOR inhibition on diverse innate immune cells
Cell typeEffects of mTORC1 inhibition upon different receptor engagementsProposed molecular mechanismSpeciesReference
  1. DCs = dendritic cells; IL = interleukin; IRF-7 = interferon regulatory factor 7; NF-κB = nuclear factor kappa B; NK cell = natural killer cell; STAT3 = signal transducer and activator of transcription 3; TLR = toll-like receptor; TNF = tumor necrosis factor.

  2. Note: The immunological consequences of mTOR inhibition such as cytokine production and T-cell stimulation may differ when freshly isolated versus in vitro-generated innate immune cells are employed. The proposed signaling alterations upon rapamycin treatment including alterations of transcription factor activity (e.g. NF-κB, STAT3, IRF-7), signaling molecules (e.g. ST2L) or cytokine alterations (e.g. reduced IL-10) may underlie the observed immunological consequences of mTOR inhibition.

Monocytes/macrophages peripheral myeloid DCsTLR2 and 4: IL-12/IL-23[UPWARDS ARROW], IL-1β[UPWARDS ARROW], IL-6[UPWARDS ARROW], TNF-α[UPWARDS ARROW], IL-10[DOWNWARDS ARROW], antigen presentation[UPWARDS ARROW], CD80[DOWNWARDS ARROW]/CD86[UPWARDS ARROW], T-cell stimulatory capacity[UPWARDS ARROW]NF-κB[UPWARDS ARROW], STAT3 [DOWNWARDS ARROW], IL-10 [DOWNWARDS ARROW]Murine and human13,14,21,22
In vitro-generated monocyte-derived DCsTLR4/CD40L and IL-1β: IL-12/TNF-α[DOWNWARDS ARROW], IL-10[DOWNWARDS ARROW], antigen presentation & T-cell stimulation [DOWNWARDS ARROW]NF-κB[DOWNWARDS ARROW], STL2[UPWARDS ARROW]Murine and human20,23
Plasmacytoid DCsTLR9: Type I interferon and T-cell stimulation [DOWNWARDS ARROW]IRF-7 [DOWNWARDS ARROW]Murine and human12,13
NK cellsAutonomous cellular proliferation [DOWNWARDS ARROW]Cell-cycle inhibitionRat18
Endothelial cellsThrombin: ICAM-1 [UPWARDS ARROW]NF-κB[UPWARDS ARROW]Human29
image

Figure 2. A homeostatic view of mammalian target of rapamycin (mTOR) in innate and adaptive immunity. In innate immune cells, mTOR is activated after stimulation by toll-like receptor (TLR) agonists or CD40L to limit the production of proinflammatory cytokines such as IL-12/23. In addition, mTOR differentially controls costimulatory molecule expression and chemokine/chemokine receptor production. In T lymphocytes, mTOR is essential for successful cell-cycle progression subsequent to IL-2 receptor activation. Moreover, mTOR downstream of the IL-12 receptor induces the production of IFN-γ to prime a Th1-mediated adaptive response. Furthermore, activation of mTOR limits the induction of regulatory T cells (Tregs). Hence, after mTOR inhibition, opposing effects during an immune response might occur: hyperactivated antigen-presenting cells (APCs) create a proinflammatory Th1/Th17-priming environment; however, subsequently mTOR inhibition shuts off the adaptive immunity due to proliferation blockade, IFN-γ (Th1) suppression and fostering of Treg emergence.

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Although several of the inflammatory phenomena observed in mTOR-I–treated patients may now have a molecular explanation, other potential consequences from these studies may become evident. For example, specific inhibition of mTOR in innate immune cells should allow to maximally boost both antitumor as well as defined vaccine responses, if mTOR within the adaptive immune cell compartment is largely unaffected. Recent data support this concept (24) and future studies aimed at influencing mTOR in innate immune cells will likely have broad implications not only for transplantation medicine, but also for anticancer and novel vaccination strategies.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Inflammation and mTOR Inhibitor Therapy: Clinical and Experimental Data
  5. The mTOR Signaling Pathway: Molecular Basics
  6. Myeloid Phagocytes Activate mTOR to Limit Proinflammatory Responses
  7. MHC Antigen Presentation is Enhanced Under mTOR Blockade by Autophagy Induction
  8. mTOR Negatively Regulates ICAM-1 Expression in Endothelial Cells to Limit Tissue Infiltration
  9. Conclusion and Perspectives
  10. Acknowledgments
  11. References