IMMUNOLOGY

A metabolic switch to memory

"Martin Prlic and Michael J. Bevan"

Two therapeutic drugs have been found to enhance memory in immune cells

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

(page 103) and Araki et al.3 (page 108) 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

(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