called T cells, apparently by altering cellular metabolism. Are changes in
T-cell metabolism the key to generating long-lived immune memory?
T lymphocytes respond to an acute infection with a massive burst of proliferation, generating effector T cells that counteract the pathogen. When the infection is cleared, most of these effector T cells die (the contraction phase of the immune response), but a minority lives on and changes into resting memory T cells that rapidly respond to future encounters with the same pathogen1. In this issue, Pearce et al.2 and Araki et al.3 report that two drugs, one used to control diabetes and the other to prevent organ-transplant rejection, markedly enhance memory T-cell development. Through their actions on major metabolic pathways in the cell, these drugs seem to promote the switch from growth to quiescent survival.
While investigating the role of a protein called TRAF6, which is a negative regulator of T-cell signalling, Pearce et al.2 noted that, although T cells in which TRAF6 was knocked out mounted a normal effector response to a pathogen, they left behind few if any memory cells. The authors performed a microarray analysis comparing the genes expressed by normal and TRAF6-deficient T cells at the time they change from effector to memory cells. In a eureka moment, they realized that TRAF6-knockout T cells display defects in the expression of genes involved in several metabolic pathways, including the fatty-acid oxidation pathway, implying that a metabolic switch in T cells might be affecting memorycell generation.
Pearce et al. followed up on this clue, and showed that the inability of TRAF6-deficient T cells to spawn long-lived memory T cells could be reversed by treatment with either the antidiabetes drug metformin or the immunosuppressant rapamycin. Both drugs are known to affect cellular metabolism, and treatment with either drug not only restored the memory T-cell response in TRAF6-deficient cells, but also greatly enhanced memory T-cell formation in normal cells, resulting in a superior recall response to a second infection.
In an independent study, Araki et al.3 examined the effect of treating mice with rapamycin during the various phases of a T-cell response to viral infection. Giving rapamycin during the first 8 days after infection (the proliferative phase) markedly increased the number of memory T cells 5 weeks later. This was due to an enhanced commitment of effector T cells to become memory precursor cells. When the authors administered rapamycin during the contraction phase of the T-cell response (days 8–35 after infection), the number of memory T cells did not increase, but there was a speeding up of the conversion of effector T cells to long-lived memory T cells with superior recall ability. Rapamycin inhibits mTOR (‘mammalian target of rapamycin’), a protein-kinase enzyme found in at least two multiprotein complexes— mTORC1, which is rapamycin sensitive, and mTORC2, which is largely resistant to inhibition by rapamycin4. To pinpoint the cellular target of rapamycin in their studies, Araki et al.3 used RNA-interference knockdown techniques to demonstrate that the mTORC1 complex, acting intrinsically in T cells, regulates memory-cell differentiation.
So both rapamycin and metformin seem to enhance T-cell memory formation. But do both drugs affect the same pathway(s), are the pathways interconnected, or do two different mechanisms lead to a similar outcome? Metformin activates AMPK, an enzyme that can inhibit mTOR activity in several ways, including directly targeting raptor, a component of rapamycin-sensitive mTORC1 (ref. 5). Both AMPK and mTOR sense and control the energy status of a cell (ATP:AMP ratio) and regulate key aspects of cell growth and, as part of this, glucose metabolism.
In a quiescent cell, most energy (in the form of ATP) is generated in the mitochondria through oxidative phosphorylation, including the oxidation of fatty acids and amino acids — catabolic metabolism. On activation, T cells massively increase their glucose uptake and shift to producing ATP by glycolysis (anabolic metabolism) instead of catabolically. mTOR is activated by signaling molecules, growth factors and antigen-induced T-cell-receptor signalling, and its activity enables a cell to increase glycolysis and ATP accumulation, which opposes AMPK activation6. Although some of the processes involved in the switch from catabolic to anabolic metabolism are fairly well understood, the reversal from an anabolic to a catabolic state is not as well characterized. One could speculate that rapamycin and metformin facilitate the switch from a glucose-dependent anabolic state (effector T cell) to a catabolic state of metabolism (memory T cell) by blocking mTORC1 activity. But how a change in the metabolic signature of a T cell could enhance memory T-cell numbers and function is unknown.
How can rapamycin, a drug known for its immunosuppressive effects, enhance the function and formation of T-cell memory? The answer may lie in dosage and, more importantly, timing. Whereas treatment with a low dose of rapamycin during the first 8 days after T-cell activation enhanced the numbers and function of memory T cells, a higher dose, closer to therapeutic levels, hampered the T-cell response, as would be expected of an immunosuppressant3. Interestingly, both papers2,3 clearly show that the higher dose of rapamycin enhanced memory T-cell function and recall ability if administered after day 8. At this point, the vigorous cell proliferation that is characteristic of the effector stage has ceased and cells begin to enter the more quiescent memory state. Recent data4 suggest that mTOR can form different complexes (aside from mTORC1 and mTORC2) depending on the phase of the cell cycle, and little is known about their inter action with rapa mycin. In addition, as the metabolic signature of a cell changes along with its activation state, rapamycin might differentially affect a cell depending on its cell cycle and metabolic state.
A long-standing paradigm in immunology proposes that, after the peak of the proliferative response, the programmed cell death of effector T cells is caused by a lack of growth also affect cell metabolism. However, recent experiments7 indicate that, in a physiological setting, effector T-cell viability and conversion to memory T cells are not regulated by competition for growth and survival factors. Thus, it is more likely that the metabolic switch is either programmed early after T-cell activation or occurs as a secondary effect after a quiescent stage has been entered. Both Pearce et al.2 and Araki et al.3 establish a crucial role for mTOR-mediated metabolic changes in enhancing T-cell memory. Does changing the metabolism of T cells through manipulation of mTOR hold promise for improving future vaccination strategies? mTOR is involved in regulating a plethora of functions in many cell types, and rapamycin administration is associated with many side effects. Thus, a more targeted approach will be required to harness their memory-enhancing ability. Identifying the downstream signaling pathways that lead to enhanced T-cell memory on inhibition of mTOR complexes will be a first step in that direction.
The metabolic state of T-cell memory. Naive T cells that have not been exposed to antigen are quiescent, but undergo metabolic conversion (catabolic metabolism to anabolic metabolism) on stimulation with an antigen such as a pathogen. This switch allows effector T cells to use mTORC1-dependent glycolytic energy production (anabolic metabolism) to sustain rapid proliferation and biosynthetic needs. At the end of the effector stage, T cells either die by programmed cell death or enter the quiescent memory stage and switch back to catabolic metabolism. Pearce et al.2 and Araki et al.3 show that rapamycin and metformin can enhance memory T-cell formation by inhibiting the protein complex mTORC1, thus leading to changes in cell metabolism
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