T lymphocytes counteract infections by generating high numbers of pathogen-specific effector T cells. Subsidence of infection leads to contraction of the lymphocyte response, in other words, the die-out of most of these effector T cells. Long-term immunological memory is thus achieved via transformation of a few surviving effector cells into resting memory T cells, which can quickly proliferate when re-exposed to the original pathogen. Two reports published in Nature demonstrate that rapamycin decreases the contraction of the CD8+ T-cell response and increases the differentiation of effector T cells into potent memory T cells.1, 2
Several novel immunosuppressive drugs have become available, increasing the number of alternatives to calcineurin inhibitor therapy and the associated adverse effects. Inhibitors of mTOR, such as rapamycin (sirolimus) and RAD001 (everolimus), were considered one of the most promising classes of immunosuppressants. The essential role of mTOR in regulating the cell cycle of proliferating cells provides the rationale for using mTOR inhibitors to block lymphocyte proliferation upon cytokine engagement. Moreover, since the mTOR signaling pathway has been shown to be dysregulated in a variety of malignant cells, mTOR inhibitors have been hypothesized to possess anticancer properties. Most of the early promises of mTOR inhibitors, however, have not been fulfilled. Apart from irritating adverse effects such as nephrotoxicity, especially when given in combination with calcineurin inhibitors, and myelotoxicity,3 the transplantation community was confronted with various inflammatory reactions and a low immunosuppressive potency. The largest prospective, controlled trial in renal transplant recipients, the ELITE-Symphony Study, revealed that the incidence of acute rejections was higher in patients administered rapamycin than in those administered either tacrolimus or ciclosporin.4 Other controlled studies have revealed that mTOR inhibition is associated with an increase in acute rejection rates. On the other hand, conversion from ciclosporin to rapamycin was associated with a restoration of Kaposi-sarcoma-specific memory T cells.5 mTOR inhibition also had potent anti-cytomegalovirus effects in patients with allogeneic transplants, even in those with ganciclovir-resistant infections.6
Results from basic immunological research might improve our understanding of the often ambiguous effects of mTOR inhibition in clinical transplantation. Koichi Araki and colleagues1 analyzed the influence of mTOR inhibition on CD8+ T-cell responses in both murine and primate models. To their surprise, the researchers observed that the CD8+ T-cell response to various viral stimuli, including hepatitis B, was enhanced—not suppressed—by treatment with rapamycin. Administration of rapamycin to mice during acute infection led to a decreased contraction of the lymphocyte response in the aftermath of antigenic stimulation, possibly via enhanced survival of antigen-specific CD8+ T cells and increased differentiation of effector cells into potent memory T cells. Importantly, rapamycin-treated lymphocytes exhibited improved functional qualities, such as optimized recall responses and increased protective properties against viral infections. Of note, rapamycin also enhanced recall responses when the drug was only administered after secondary viral infection, which means that mTOR is pivotal in regulating memory formation during both primary and secondary CD8+ T-cell responses. Finally, memory responses were enhanced even when rapamycin was continually administered, and, more than 165 days after stopping drug treatment, memory T cells were about tenfold more numerous in rapamycin-treated mice than in rapamycin-naive ones. In the same issue of Nature, Erika Pearce and colleagues2 investigated the consequences of a deficiency in a negative regulatory transcription factor encoded by TRAF6 in murine cells. Although the initial phenotype of these mice was unremarkable, their immune system lacked an adequate memory response. Employing microarray analysis, the researchers found that TRAF6-knockout T cells exhibited defects in various metabolic pathways. Treatment of TRAF6-knockout T cells with rapamycin not only restored effective T-cell memory but also greatly enhanced recall responses compared with TRAF6-knockout cells not treated with rapamycin.
As mTOR is an evolutionary-conserved nutrient sensor, these results suggest that mTOR inhibition alters T-cell activation by inducing metabolic changes at the peak of anabolic metabolism associated with effector T-cell production and at the subsequent stage in which memory lymphocytes revert to catabolic metabolism. As concluded by Araki et al., inhibition of mTOR might be a potent strategy to maximize the efficiency of vaccines against diseases such as HIV, malaria and tuberculosis. In fact, optimization of tuberculosis vaccination has already been demonstrated after ex vivo priming of dendritic cells with rapamycin and mycobacterial antigens.7 Weichhart et al.8 demonstrated that mTOR negatively regulates proinflammatory cytokine production in monocytes, macrophages and peripheral dendritic cells following contact with Gram-negative and Gram-positive stimuli. Hence, inhibition of mTOR in these cells superactivates the proinflammatory protein complex transcription factor NF
B but blocks the anti-inflammatory transcription factor encoded by STAT3, thereby increasing the production of proinflammatory cytokines such as interleukin 12, interleukin 23 and tumor necrosis factor but suppressing antiinflammatory cytokines like interleukin 10 (Figure 1).
Figure 1 | Consequences of mTOR inhibition in different immunocompetent cells.
Note that downward arrows next to the names of proteins or genes represent downregulation and upward arrows represent upregulation. *Increased numbers and potency. Abbreviations: FOXP3, FOXP3 protein; IL, interleukin; TNF, tumor necrosis factor; TREG, regulatory T cells.
The immunostimulatory properties of rapamycin have to be balanced against the role of mTOR in the induction of regulatory T cells (TREG), which cause the downregulation of antigen-specific immune responses, a primary clinical target in allogeneic transplantation. Pharmacological inhibition or genetic ablation of mTOR might induce the pivotal TREG-specific transcription factor FOXP3 protein in effector CD4+ T cells, thereby fostering the differentiation of helper T cells into TREG.9 Although fostering TREG production by mTOR inhibitors in murine transplant models extended allograft survival, a study in human renal transplant recipients was not able to show that rapamycin ameliorates chronic allograft injury despite the induction of significant numbers of CD4+ and CD25+ TREG.10
These findings make reference to mTOR inhibitors as simple cell-cycle blocking immunosuppressants no longer possible. The adverse effects and seemingly weak efficiency of rapamycin in transplant recipients might reflect the highly divergent functions of mTOR in different immunocompetent cells (Figure 1). Maybe we can be more explicit and state that the recognition that targeting mTOR also boosts innate and adaptive effector arms of the immune system should lead the nephrology community to reconsider whether rapamycin should have an important role in clinical transplantation, or whether its use should instead be confined to exceptional cases.
