Download mTORC1 regulates CD8 T-cell glucose metabolism and function

Regulation of Metabolism in Cancer and Immune Cells
mTORC1 regulates CD8 + T-cell glucose metabolism
and function independently of PI3K and PKB
David K. Finlay1
School of Biochemistry and Immunology, and School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin,
Dublin 2, Ireland
Abstract
Given that inflammatory T-cells have a highly glycolytic metabolism, whereas regulatory T-cells rely more
on oxidative glucose metabolism, there is growing interest in understanding how T-cell metabolism relates
to T-cell function. The mTORC1 (mammalian target of rapamycin complex 1) has a crucial role to determine
the balance between effector and regulatory T-cell differentiation, but is also described as a key regulator
of metabolism in non-immune cell systems. The present review explores the relationship between these
diverse functions of mTORC1 with regard to T-cell function. In many cell systems, mTORC1 couples PI3K
(phosphoinositide 3-kinase) and PKB (protein kinase B), also known as Akt, with the control of glucose
uptake and glycolysis. However, this is not the case in activated CD8 + CTLs (cytotoxic T-lymphocytes) where
PI3K/PKB signalling is dispensable for the elevated levels of glycolysis that is characteristic of activated
T-cells. Nevertheless, mTORC1 is still essential for glycolytic metabolism in CD8 + T-cells, and this reflects
the fact that mTORC1 does not lie downstream of PI3K/PKB signalling in CD8 + T-cells, as is the case in
many other cell systems. mTORC1 regulates glucose metabolism in CTLs through regulating the expression
of the transcription factor HIF1α (hypoxia-inducible factor 1α). Strikingly, HIF1α functions to couple mTORC1
with a diverse transcriptional programme that extends beyond the control of glucose metabolism to the
regulation of multiple key T-cell functions. The present review discusses the idea that mTORC1/HIF1α
signalling integrates the control of T-cell metabolism and T-cell function.
mTORC (mammalian target of rapamycin
complex) 1 signalling and function
mTOR (mammalian target of rapamycin) is a serine/
threonine kinase with important functions for a range of
cellular processes. mTOR forms two distinct multiprotein
complexes, mTORC1 and mTORC2, with only mTORC1
being acutely sensitive to the inhibitor rapamycin [1].
mTORC1 integrates inputs from major cellular signals
including growth factors, energy status, oxygen and amino
acids to promote cell growth and function. One of the
dominant mechanisms through which these signals control
mTORC1 activity is through modulating the function of the
TSC2 (tuberous sclerosis complex 2), which acts as a GTPaseactivating protein for the small GTPase Rheb. TSC2 regulates
mTORC1 negatively by promoting the conversion of Rheb
to its inactive GDP-bound state. Therefore, when the cellular
energy status is compromised, AMPK (AMP-activated
protein kinase) is active to phosphorylate and activate TSC2,
thus inhibiting mTORC1 activity. Conversely, growth factors
Key words: cytotoxic T-lymphocyte, glycolysis, hypoxia-inducible factor 1α (HIF1α), mammalian
target of rapamycin complex 1 (mTORC1), protein kinase B (PKB), trafficking.
Abbreviations used: AGC family, protein kinase A/protein kinase G/protein kinase C family;
CCR7, CC chemokine receptor 7; CTL, cytotoxic T-lymphocyte; FOXO, forkhead box O; Glut1,
glucose transporter 1; HIF1, hypoxia-inducible factor 1; IFNγ , interferon γ ; IL-2, interleukin2; mTOR, mammalian target of rapamycin; mTORC, mTOR complex; PDK1, phosphoinositidedependent kinase 1; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PKC, protein kinase
C; RSK, 90 kDa ribosomal S6 kinase; S6K, 70 kDa ribosomal S6 kinase; SGK, serum/glucocorticoidregulated kinase; TCR, T-cell receptor; TSC2, tuberous sclerosis complex 2.
1
email fi[email protected]
Biochem. Soc. Trans. (2013) 41, 681–686; doi:10.1042/BST20120359
induce the activity of multiple kinases, including PKB
(protein kinase B), also known as Akt, which phosphorylate
and inhibit TSC2 to promote mTORC1 activity. PKB,
activated downstream of PI3K (phosphoinositide 3-kinase),
also regulates mTORC1 in a TSC2-independent manner by
phosphorylating the mTORC1 inhibitor PRAS40 (prolinerich Akt substrate of 40 kDa), inducing its dissociation from
mTORC1 [1]. Whereas in lymphocytes PI3K/PKB signalling
is frequently considered an upstream obligatory regulator of
mTORC1 activity in response to diverse stimuli [2–4], the
present review describes how this is not always the case.
Multiple roles for mTORC1 have been described in
the regulation of various aspects of cellular metabolism.
mTORC1 activity promotes various anabolic processes
including protein synthesis, glycolysis and lipid synthesis
while inhibiting catabolic processes such as autophagy.
Although mTORC1 regulation of these processes appears to
be rather complex, certain key mTORC1 effectors have been
identified. mTORC1 is linked to the control of glycolysis
through two distinct transcription factors, i.e. c-Myc and
HIF (hypoxia-inducible factor) 1α, each of which promote
the expression of multiple glycolytic enzymes and glucose
transporters. mTORC1 activity has also been linked to
the control of lipid synthesis through the SREBP (sterolregulatory-element-binding protein) 1 and 2 transcription
factors that control the expression of enzymes required for
fatty acid and cholesterol synthesis. Additionally, mTORC1
activity also regulates autophagy negatively through the
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Figure 1 mTORC1 controls T-cell glucose metabolism
Naive T-cells take up small amounts of glucose, which is for the most part metabolized to CO2 via mitochondrial OxPhos
(oxidative phosphorylation) for the efficient generation of ATP. Activated T-cells increase the expression of Glut1 and thus
glucose uptake, and increase glycolytic flux, primarily converting glucose into lactate. This metabolic switch increases the
biosynthetic capacity of these T-cells and is stimulated by TCR activation and maintained by certain cytokines including IL-2.
mTORC1/c-Myc signalling promotes this metabolic shift in response to TCR stimulation, whereas mTORC1 signalling through
HIF1α promotes CTL glycolytic metabolism in response to IL-2.
phosphorylation and inactivation of Ulk1, a kinase that
promotes autophagosome formation [1].
In T-lymphocytes, the best characterized role for
mTORC1 is in the regulation of T-cell fate and function.
mTORC1 promotes the differentiation of effector CD4 + Tcell subsets over regulatory CD4 + T-cells and also promotes
effector CD8 + CTL (cytotoxic T-lymphocyte) development
over CD8 + memory T-cells [4]. However, until recently,
a role for mTORC1 in controlling T-cell metabolism has
not been appreciated. Neither has the relationship between
these apparently distinct roles for mTORC1 in controlling
metabolism and cellular function been considered.
T-cell metabolism
Although naive T-cells only require energy to prevent
atrophy and for survival and migration, activated T-cell
subsets have a greatly increased metabolic demand as they
engage in rapid growth and proliferation, and the production
of cytokines and other effector molecules. It is crucial
that activated T-cells increase their metabolism to meet
the biosynthetic needs of the T-cell as it responds either
to developmental or pathogenic cues. To achieve this,
T-cells respond to extrinsic signals from antigen receptors
and cytokines to up-regulate the surface expression of key
nutrient receptors: amino acid transporters, the transferrin
receptor and glucose transporters [5–7]. Additionally,
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Authors Journal compilation T-cells switch their glucose metabolism from oxidative phosphorylation to aerobic glycolysis, i.e. glucose is metabolized
to produce lactate even though oxygen is readily available [8].
Aerobic glycolysis is an inefficient route to generating ATP,
producing only two molecules of ATP/glucose compared
with >30 molecules of ATP/glucose generated by oxidative
phosphorylation. Therefore cells must be able to sustain
high levels of glucose uptake and an elevated glycolytic flux
to generate a sufficient amount of ATP (Figure 1). This
is achieved by increasing the expression of Glut1 (glucose
transporter 1) and certain rate-limiting enzymes within the
glycolytic pathway [9,10]. However, the real advantage of
switching from oxidative phosphorylation to glycolysis is
that it allows glucose to be used as a source of carbon to
generate nucleic acids, amino acids and phospholipids [10].
The generation of these biosynthetic precursors is critical
for cells engaging in rapid growth, proliferation and the
synthesis of effector molecules. Therefore, to facilitate their
differentiation and function, activated T-cells up-regulate the
expression of Glut1, increase glucose uptake and activate
the switch to aerobic glycolysis [8,11–13].
The metabolic switch to aerobic glycolysis is initiated
by TCR (T-cell receptor) activation and then maintained
in certain T-cell subsets by cytokines such as IL-2
(interleukin-2) and is crucial for normal T-cell activation
and differentiation in the periphery. Thus limiting glucose
availability in activating T-cells compromises TCR-induced
Regulation of Metabolism in Cancer and Immune Cells
growth and proliferation and also the expression of certain
effector molecules such as perforin and IFNγ (interferon γ )
[5,14]. Therefore it appears that a highly glycolytic metabolic
profile is associated with inflammatory T-cell subsets, CD4 +
Th1, Th2 and Th17 T-cell subsets and CD8 + CTLs, but not
CD4 + Tregs (regulatory T-cells) or CD8 + memory T-cells
[15–18]. The transcription factor c-Myc is crucial for the
metabolic switch in glucose metabolism that accompanies
the activation of naive T-cells [19]. Accordingly, deletion
of c-Myc in naive T-cells prevents TCR-induced glucose
uptake and glycolysis, and activated c-Myc-null T-cells
completely fail to grow or proliferate [19–22]. However,
in activated CD8 + CTLs, elevated glucose uptake and
glycolysis is maintained by IL-2 independently of c-Myc
[17]. In CTLs, the critical transcription factor that is required
to promote glucose uptake and glycolysis is the HIF1α–
HIF1β transcriptional complex. Thus deletion of HIF1β
alleles results in decreased Glut1 expression and glycolysis
in CD8 + CTLs [17].
mTORC1, but not PI3K or PKB, controls
T-cell glucose metabolism
What are the signalling pathways that control glucose
metabolism in activated T-cells? Antigen receptor-induced
c-Myc expression and glucose uptake was originally attributed to PI3K and PKB signalling [5,11,19,23,24]. However,
one criticism of these studies is that they rely on experiments
involving the use of the PI3K inhibitor LY294002, which
also inhibits various other kinases including mTORC1 [25–
27]. A more thorough analysis of PI3K/PKB signalling using
pharmacological inhibitors of PI3Kδ (IC87114) and PKB
(Akti1/2) with substantially greater selectivity than LY294002
[28–30] has shown that PI3K/PKB activities are dispensable
for increased glucose uptake and glycolysis in TCR-activated
T-cells [17,28]. Once activated, T-cells differentiate into
various different effector T-cell subsets depending on the
local environment and cytokine availability. In CD8 + CTLs
responding to the cytokine IL-2, it is also apparent that
glucose uptake and glycolysis is maintained independently of
PI3K and PKB [17]. Instead, mTORC1 is the key regulator of
both TCR- and IL-2-induced glucose metabolism in CD8 +
T-cells. Thus mTORC1 activity is required for TCR-induced
c-Myc expression and the switch to increased glycolysis
[17,19] (Figure 1). Likewise, inhibition of mTORC1 in IL2-maintained CTLs results in decreased glycolysis, in this
instance, as a result of the loss of HIF1α expression [17]
(Figure 1). Indeed, inhibition of mTORC1 also decreases
glycolysis in CD4 + T-cells activated under Th17-polarizing
conditions [15], thus emphasizing the importance of this
kinase in promoting glycolysis in T-cells.
However, as stated above, lymphocyte signalling models
position PI3K/PKB signalling as an upstream obligatory
regulator of mTORC1 activity [2–4], which is inconsistent
with the observation that mTORC1, but not PI3K/PKB,
signalling promotes glycolysis in T-cells [17,28]. This
apparent contradiction is redressed by the recent revelation
that in CD8 + T-cells, mTORC1 activity is in fact maintained
independently of PI3K and PKB [17]. Thus mTORC1
activity is unaffected when PI3K or PKB activity is disrupted
by either pharmacological or genetic perturbations [17]. If
not PI3K/PKB, what signalling pathways are responsible
for mTORC1 activation in CTLs? A key role has been
identified for PDK1 (phosphoinositide-dependent kinase
1), a kinase responsible for the phosphorylation and
activation of multiple members of the AGC family [protein
kinase A/protein kinase G/PKC (protein kinase C)
family] kinases including PKB, PKC, S6K (70 kDa ribosomal
S6 kinase), RSK (90 kDa ribosomal S6 kinase) and SGK
(serum/glucocorticoid-regulated kinase) [31]. As members of
this kinase family have overlapping substrate specificity [32–
35] (Figure 2), it is likely that PDK1-dependent and PKBindependent regulation of mTORC1 and glucose metabolism
reflects functional redundancy within the AGC family of
protein kinases with regard to the activation of mTORC1,
although the exact mechanism has yet to be determined.
Indeed, consistent with this role for PDK1 in the activation of
mTORC1, PDK1-deficient CTLs have reduced HIF1α and
Glut1 expression, and decreased levels of glucose uptake
and glycolysis [17,28].
mTORC1 and HIF1 integrate T-cell
metabolism and function
IL-2 sustains elevated levels of glucose metabolism and
glycolysis in CD8 + CTLs by maintaining mTORC1 activity
and the protein expression of HIF1α [17]. In fact, HIF1
functions to couple mTORC1 to a diverse transcriptional
programme that extends beyond the control of glucose
metabolism [17]. Thus, although mTORC1/HIF1 controls
expression of glucose transporters and multiple rate-limiting
glycolytic enzymes, this signalling axis also regulates the
expression of cytolytic effector molecules and essential
chemokine and adhesion receptors that regulate T-cell
trafficking [17]. CTLs deficient for HIF1α–HIF1β transcriptional complexes fail to express a discrete subset of effector
cytolytic molecules including granzymes and perforin while
maintaining normal expression of IFNγ , TNFα and lymphotoxins [17]. HIF1-null CTLs also retain the expression
of key lymph node homing receptors CD62L (also called
L-selectin) and CCR7 (CC chemokine receptor 7) and have
an altered trafficking profile relative to wild-type CTLs,
homing preferentially to lymph nodes rather than sites of
inflammation [17].
The observation that mTORC1/HIF1 controls T-cell
trafficking through regulating the expression of CD62L
and CCR7 raises the question of how this mTORC1/HIF1
pathway connects to a well-documented PI3K/PKB/FOXO
(forkhead box O) pathway that also controls the expression
of these key trafficking molecules [36]. The retention of
high levels of CCR7 and CD62L expression by immuneactivated HIF1-null CD8 + T-cells phenocopies the impact
of inhibiting PI3K/PKB signalling in activated CD8 +
T-cells [28,37,38]. PI3K/PKB-regulated CD62L and CCR7
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Figure 2 PDK1 mediated activation of the AGC family of protein kinases
PI(4,5)P2 (phosphoinositide 4,5-bisphosphate) is phosphorylated by PI3K generating the second messenger molecule
PI(3,4,5)P3 (phosphoinositide 3,4,5-trisphosphate). Binding of the PH (pleckstrin homology) domain of PKB to PI(3,4,5)P3
in the membrane results in a conformational change that allows for the phosphorylation of PKB by PDK1. The recruitment
of PDK1 via its PH domain to the site of PI(3,4,5)P3 is required for efficient PKB activation. PDK1 also phosphorylates
and activates numerous other members of the AGC family of protein kinases including PKC, S6K, RSK and SGK. Although PDK1
activation of PKB requires PI3K activity, PDK1 activation of these other AGC family kinases is independent of PI3K activity.
There are multiple examples of overlapping substrate specificity within this family of protein kinases with respect to S6 (S6
ribosomal protein), GSK3 (glycogen synthase kinase 3), TSC2 and FOXO transcription factors.
Figure 3 PKB and mTORC1 are activated separately, but have
convergent functions
PKB and mTORC1 are activated separately in CTLs, but converge through
distinct mechanisms to regulate key CTL effector molecules (perforin,
granzyme and IFNγ ) and CD8 + T-cell trafficking. Continuous lines
represent direct regulation.
reflects that the expression of these molecules is regulated
by the FOXO1 transcription factor [39,40]. FOXO1 is phosphorylated by PKB on multiple residues resulting in FOXO1
nuclear to cytoplasmic translocation, thus inhibiting
FOXO1 transcriptional activity. Inhibition of PKB in CTLs
results in the dephosphorylation of FOXO1, restoring
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Authors Journal compilation FOXO1 nuclear localization, FOXO1 transcriptional activity and the expression of CD62L and CCR7 [28,37]. To date,
the effect of mTORC1 inhibition on T-cell trafficking has
been attributed to the observation that, in some cells, longterm rapamcyin treatment can result in PKB inhibition via
disruption of mTORC2, which would be predicted to result
in nuclear translocation of FOXO1 and the expression of
CD62L and CCR7. However, this is not the case and FOXO1
cellular localization is unaffected in rapamycin-treated CTLs
or indeed in HIF1-null CTLs [17].
Although HIF1 directly regulates the transcription of
glucose transporters and glycolytic enzymes, it appears likely
that mTORC1/HIF1 regulation of CTL effector molecules is
indirect and potentially a secondary event to altered glucose
metabolism. In support of this idea, CTLs cultured in limiting
glucose concentrations or treated with 2-deoxyglucose lose
the expression of perforin molecules [14,17], whereas CTLs
deprived of glucose also maintain high levels of CD62L
expression [17].
mTORC1 and PKB are activated
independently, but have convergent
functions
mTORC1/HIF1 regulates CTL trafficking through a mechanism that is independent of FOXO transcription factors.
Therefore PKB and mTORC1 are activated independently
in CTLs, but converge to regulate T-cell trafficking through
distinct signalling pathways (Figure 3). Indeed, PKB/FOXO
Regulation of Metabolism in Cancer and Immune Cells
and mTORC1 signalling also converge to regulate other key
T-cell functions. PI3K/PKB and mTORC1 signalling both
promote IFNγ expression through distinct mechanisms that
differ in the requirement for FOXO transcription factors
[28,41]. Additionally, both PKB and mTORC1 signalling are
required for the expression of the cytolytic molecules perforin
and granzyme in CD8 + CTLs [17,28] (Figure 3).
Therefore PKB and mTORC1 are activated independently,
but converge to control the expression of key molecules
required for effector CTL function. An essential requirement
for these two independent signalling pathways to control
T-cell differentiation highlights the importance of integrating
lymphocyte signal transduction for appropriate immune
responses.
Funding
D.K.F. is funded by a Marie Curie Career Integration Grant [grant
number 321603].
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Received 19 December 2012
doi:10.1042/BST20120359