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
(Fig. 1). mTOR is activated by signalling
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
(Fig. 1). 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
and survival factors — conditions that could
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 signalling
pathways that lead to enhanced T-cell memory
on inhibition of mTOR complexes will be a first
step in that direction.
Martin Prlic and Michael J. Bevan are in the
Department of Immunology, University of
Washington, Seattle, Washington 98195-7370,
USA.
e-mails: mprlic@u.washington.edu;
mbevan@ u.washington.edu
