1 s2.0 S1550413120303119 Main

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Amino Assets: How Amino Acids Support Immunity
Beth Kelly1 and Erika L. Pearce1,*
1Max Planck Institute for Immunobiology and Epigenetics, Freiburg 79108, Germany
*Correspondence: [email protected]
https://doi.org/10.1016/j.cmet.2020.06.010
Amino acids are fundamental building blocks supporting life. Their role in protein synthesis is well defined,
but they contribute to a host of other intracellular metabolic pathways, including ATP generation, nucleotide
synthesis, and redox balance, to support cellular and organismal function. Immune cells critically depend on
such pathways to acquire energy and biomass and to reprogram their metabolism upon activation to support
growth, proliferation, and effector functions. Amino acid metabolism plays a key role in this metabolic rewir-
ing, and it supports various immune cell functions beyond increased protein synthesis. Here, we review the
mechanisms by which amino acid metabolism promotes immune cell function, and how these processes
could be targeted to improve immunity in pathological conditions.
Introduction different ATP-producing pathways, such as glycolysis and mito-

Amino acids are fundamental units that supported the earliest life chondrial metabolism, via the tricarboxylic acid (TCA) cycle and
on earth. Individual amino acids can be created abiotically and oxidative phosphorylation (OXPHOS). And as reactive oxygen
have been detected in extraterrestrial sources such as meteor- species (ROS) production is a key step in immune cell activation,
ites (Burton et al., 2012). A major evolutionary step was the ability we describe how amino acids are central regulators of redox bal-
to combine amino acids into peptides and then proteins, which ance within immune cells, and how sulfur supply from cysteine
mediate cellular functions. In addition to protein synthesis, amino and methionine may determine continued metabolic and transla-
acids are used for many other processes driving growth and pro- tional activity in cells with altered redox status. Further, we re-
liferation. Amino acid metabolism has profound consequences view how amino acids tune immune effector protein activity by
for cell function, not the least of which include that of immune supplying intermediates, such as methyl and acetyl groups, for
cells, which are critically dependent on metabolic status due to post-translational modification (PTM), and how such intermedi-
their dynamic activation states as they respond to infections ates also epigenetically regulate acute immune responses and
and changes in their tissue environments (Buck et al., 2017). immune cell memory. Finally, we investigate amino acid compe-
Amino acids are a key nutrient for immune cells, and amino tition between immune and tumor cells, and explore how target-
acid supply instructs immune cell function. Immune cells have ing amino acid metabolism could modulate immune responses
specific amino acid requirements, while growth factor stimula- in cancer, infection, and autoimmunity.
tion and activation of T cells, which induce their rapid prolifera-
tion, increase amino acid transporter expression (Geiger et al., Acquisition and Sensing of Amino Acids
2016; Ron-Harel et al., 2019; Sinclair et al., 2019), illustrating An amino acid is an organic molecule containing an amino group
the need for enhanced amino acid uptake during this process. and a carboxyl group attached to a carbon atom. Each amino
Upon activation, T cells rapidly proliferate and undergo acid also has a unique side chain, which bestows different prop-
increased gene transcription-translation for critical immune- erties and functions (Wu, 2009). A limited set of 10 amino acids,
related responses, such as cytokines and adhesion molecules, produced by abiotic chemical or physical reactions, may have
and thus must upregulate protein synthesis. Such responses been used for very early proteinogenesis before cellular biosyn-
are metabolically demanding, as new DNA, proteins, nucleo- thesis evolved (Frenkel-Pinter et al., 2019; Longo and Blaber,
tides, and other biomolecules must be produced before cells 2012). A consensus set of these 10 early amino acids comprises
can divide and mount an immune response. However, it is now alanine, aspartate, glutamate, glycine, isoleucine, leucine, pro-
appreciated that amino acids have multiple signaling roles and line, serine, threonine, and valine (Doi et al., 2005b), while the
supply material for more than just energy and protein synthesis. more complex aromatic amino acids tryptophan and phenylala-
In this review, we explore how amino acids go beyond merely nine, and the sulfurous amino acid methionine, arose later
supporting protein synthesis to control immune cell function. We (Longo et al., 2015). Mammals use a set of 20 amino acids for
examine how different immune cells selectively acquire amino protein synthesis, though many more exist in nature and influ-
acids, rather than their indiscriminate uptake, downstream of an- ence cell function (Schuller-Levis and Park, 2003). Nine of these
tigen and cytokine signaling and the control of amino acid trans- 20 proteinogenic amino acids are known as essential amino
porter expression. We then discuss how amino acids support the acids, as they cannot be sufficiently synthesized by the body
metabolic reprogramming critical for immune cell activation. In and must be acquired from dietary sources (Wu, 2013). In
addition, we expand on the idea that amino acids are not just contrast, non-essential amino acids can be synthesized to suffi-
used for the end result of this reprogramming, i.e., increased cient levels in the body and do not need to be acquired, but can
biosynthesis to drive proliferation and effector molecule produc- become conditionally essential under conditions in which de-
tion. Instead, they control these metabolic switches by feeding mand exceeds the body’s capacity for synthesizing them
154 Cell Metabolism 32, August 4, 2020 ª 2020 Elsevier Inc.

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(Combs and DeNicola, 2019; Wu, 2013). This dependence oc- porter repertoire, CD4+ T cells have a lower copy number of
curs in rapidly proliferating cells (Curthoys and Watford, 1995), these transporters and less nutrient transport (Howden et al.,
which need amino acids for protein synthesis and increased 2019; Sinclair et al., 2013; Swamy et al., 2016). This difference,
biomass (Hosios et al., 2016). Given the marked changes in in combination with the lower levels of ribosomes and transla-
cell growth and proliferation that are characteristic of immune tional machinery in activated CD4+ versus CD8+ T cells, could
cells responding to alterations in their extracellular environment, underlie the lower cell mass and proliferative capacity of acti-
it is likely that for these cells non-essential amino acids may vated CD4+ T cells compared to CD8+ T cells. Such a detailed
become conditionally essential during an immune response. study of changes in amino acid transporter expression in other
Acquisition of Amino Acids immune cell types would be highly informative, as their activation
Amino acid acquisition is a point of control for cell function. Up- also depends on amino acid transporter activity. Further, both
take from the external environment relies on transporters, while classical and alternative macrophage activation depend on argi-
intracellularly, amino acids are recycled and donate functional nine uptake via cationic amino acid transporter (CAT)2 (Slc7a2)
groups for other amino acids. For example, glutamine supplies (Yeramian et al., 2006b), while resting macrophages use the
amino groups for other amino acids via transamination and y+L (Slc7a6, Slc7a7) system for arginine uptake, likely via CAT1
transamidation, and methionine is metabolized to cysteine in (Slc7a1) (Yeramian et al., 2006a). Lipopolysaccharide (LPS) in-
the methionine cycle (Sinclair et al., 2019). Lysosomes also creases Slc7a5 expression and leucine uptake to support human
contain amino acid transport machinery (Sagné et al., 2001; pro-inflammatory macrophage cytokine production (Yoon et al.,
Wyant et al., 2017), and can act as intracellular amino acid de- 2018). These examples illustrate how innate immune cell activa-
pots (Abu-Remaileh et al., 2017), important for cell function. tion depends on remodeling of amino acid transporter activity.
For example, the lysosomal histidine transporter Slc15a4 is Multiple signaling pathways in turn control transporter expres-
needed for Toll-like receptor (TLR)-induced type I interferon sion. Myc, a central transcription factor driving T cell activation,
(IFN-I) production in plasmacytoid dendritic cells (pDCs), and increases Slc1a5, Slc7a1, Slc7a5, Slc38a1, and Slc38a2 on acti-
IFN-I and immunoglobulin (Ig)G production in B cells (Kobayashi vated CD4+ and CD8+ T cells (Marchingo et al., 2020). Myc defi-
et al., 2014). During starvation, amino acids are sequestered in ciency blocks activated T cell growth by reducing expression of
the lysosome, possibly to prevent their inappropriate use during these transporters to that of naive cells. TCR stimulation also
this nutrient-restricted period. One possible consequence of activates the mitogen-activated protein kinase (MAPK) family
such lysosomal amino acid storage is induction of autophagy, member extracellular signal-regulated kinase (ERK) to increase
which promotes longevity, in part by antagonizing the age- glutamine uptake (Carr et al., 2010), possibly by increasing surface
related decline in CD8+ T cell function and immune responses sodium-coupled neutral amino acid transporter (SNAT)2 (Slc38a2)
to infection and cancer (Pietrocola et al., 2016; Puleston et al., expression (Franchi-Gazzola et al., 1999). Multiple pathways con-
2014). Lysosomal storage could also provide the cell with a trol expression of individual transporters. Slc7a5 expression also
bank of amino acids that can be mobilized when protein synthe- depends on calcium-calcineurin signaling (Sinclair et al., 2013),
sis resumes, and autophagy would presumably increase amino and both ERK and c-Jun N-terminal kinase (JNK) control SNAT2
acid availability in this context. Amino acids could be selectively (Hyde et al., 2007). Differential regulation of transporters and use
released to drive particular gene expression programs to adapt of signaling pathways underlie the varying effects of cytokines
to prolonged starvation or nutrient restoration; for example, by on T cell growth and proliferation. IL-2 and IL-15 both signal
influencing epigenetic modifications. through CD122 and activate Janus kinase (JAK)1, JAK3, and
Amino Acid Transporters Control Immune Cell Function signal transducer and activator of transcription (STAT)5, but with
Amino acid uptake via transporters is a tightly regulated process different consequences for antigen-activated T cells. IL-2 pro-
that is critical for immune cell activation and function. A compre- motes CD8+ effector T (Teff) cell formation and cell growth, while
hensive proteomic analysis of human immune cells illustrated the IL-15 is needed for the formation of CD8+ memory T (Tmem) cells,
vast diversity of transporters and receptors expressed by which are smaller in size. T cells maintained in IL-2 have higher
different immune cell types, and how these transporters change CD98 (Slc7a5/Slc3a2) expression than those in IL-15, and in-
expression upon antigen stimulation and cytokine signaling crease amino acid uptake and protein synthesis, underlying the
(Rieckmann et al., 2017). This has been more specifically different effects of these cytokines on T cell growth (Cornish
explored in a proteomic analysis of CD4+ and CD8+ T cells, et al., 2006). These effects depend on sustained phosphoinosi-
which illustrated how antigen and cytokine stimulation changes tide-3-kinase (PI3K) signaling in T cells cultured in IL-2 versus
expression of amino acid transporters to alter nutrient uptake more transient PI3K signaling in IL-15-cultured cells. More work
and specifically enable effector function in activated T cells is needed to understand how divergent effects of cytokines on
(Howden et al., 2019). Activation of CD8+ T cells by T cell recep- signaling pathway activities and kinetics control immune cell
tor (TCR) stimulation in the presence of growth factor cytokines, growth via modulation of amino acid transporters.
e.g., interleukin (IL)-2, increases the density of Slc1a5 and Asymmetric Distribution of Amino Acid Transporters
Slc7a5 on the cell surface compared to naive CD8+ T cells. Acti- Influences T Cell Fate
vated T cells require a supply of amino acids to support prolifer- During an infection, a T cell population must generate Teff cells to
ation, and this activation-dependent enhancement of transporter fight the infection, as well as Tmem cells to provide long-lasting
expression ensures that cells can acquire these nutrients ac- immunity. Asymmetric cell division, in which the two daughter
cording to their demand. It is not only the type, but the level of cells generated by a cell division event adopt different fates, is
transporter expression, that influences T cell function. While acti- one model proposed for T cells to achieve this goal (Arsenio
vated CD4+ and CD8+ T cells express a similar nutrient trans- et al., 2014, 2015; Reiner and Adams, 2014). In asymmetric cell
Cell Metabolism 32, August 4, 2020 155

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division, protein, RNA, and organelles are unequally inherited by extensive proliferation, which requires acquisition of biomass
the daughter cells, laying the foundation for their different fates. for cell division. Immune cells reprogram their metabolism to
Antigen presentation by antigen-presenting cells (APCs) stimu- support these exceptionally high metabolic demands. Distinct
lates activation and proliferation of naive T cells. The T cell prox- metabolic pathways fuel different immune cells, and metabolic
imal to the APC adopts an effector-like fate, while the distal T cell reprogramming dictates immune cell survival, differentiation,
assumes a memory-like fate, based on the asymmetric inheri- and function (Geltink et al., 2018; O’Neill et al., 2016).
tance of factors, including CD3, CD4, CD8, CD62L, transcription A major requirement of activated immune cells is energy in the
factors, and mechanistic target of rapamycin (mTOR), between form of ATP. Glycolysis, the TCA cycle, and OXPHOS cooperate
the daughter cells (Chang et al., 2007). Slc1a5 is one such asym- to produce ATP, and amino acids regulate these interconnected
metrically inherited factor. Slc1a5 preferentially accumulates in processes. Glycolysis processes glucose to pyruvate, gener-
the proximal cell, which also exhibits increased amino acid abun- ating ATP and NADH, a cofactor for a multitude of enzymes,
dance, glutamine uptake, glycolysis, c-Myc, and mTOR complex including those of mitochondrial metabolism. Pyruvate-derived
(mTORC)1 activity (Verbist et al., 2016). The direct effect of acetyl-CoA enters the TCA cycle in the mitochondria to generate
Slc1a5 on c-Myc levels was not established in this system, but the reducing equivalents NADH and FADH2 that provide elec-
amino acid deprivation or blockade of glutaminolysis reduces trons for OXPHOS. Mitochondrial fatty acid oxidation (FAO)
the differences in c-Myc between the daughter cells, and yields acetyl-CoA, NADH, and FADH2, further driving mitochon-
reducing c-Myc levels pushes the daughter cells toward a mem- drial metabolism and ATP production. Amino acid metabolism
ory-like phenotype (Verbist et al., 2016). This study established contributes to these pathways (Figure 1), the differential use of
that metabolic asymmetry, specifically in terms of amino acid which dictates immune cell function (Box 1).
acquisition, may underlie different T cell fates. Similarly, Glutamine Supports Metabolic Rewiring
daughter CD8+ T cells with increased Slc7a5 expression have Glutamine provides intermediates for many metabolic pathways.
increased CD8 expression, mTORC1 activity, Myc levels, and Glutaminolysis is a major energy-producing process for prolifer-
glycolysis, while cells with lower CD8 and Slc7a5 expression ating cells, including activated T cells (Newsholme et al., 1999),
have increased mitochondrial mass. Slc7a5 inhibition, but not by supplying a-ketoglutarate (aKG) to the TCA cycle, via gluta-
mTORC1 inhibition, decreases mTORC1 lysosomal transloca- mate. Glutamine is required for T cell activation (Yaqoob and
tion in CD8hi daughter cells, indicating amino acid supply Calder, 1997), as T cells cultured without glutamine cannot
through Slc7a5 as an upstream regulator of the asymmetric proliferate or produce IL-2 or IFN-g (Carr et al., 2010). Supplemen-
division of mTORC1 activity (Pollizzi et al., 2016). Together, these tation with asparagine, proline, or glutamate, which can be metab-
results implicate amino acid metabolism and cellular metabolic olized to glutamine, does not recue proliferation or cytokine de-
profiles as determinants of cell fate. fects due to glutamine withdrawal, indicating that acquisition of
Sensing Amino Acid Supply extracellular glutamine, and not its intracellular generation, is the
Multiple mechanisms sense amino acids to control immune cell key regulatory event. This explains why naive T cell activation in-
metabolism. mTORC1 is a central cellular signaling hub that drives duces glutamine uptake, dependent on SNAT1, SNAT2 (Slc38a2)
protein synthesis, cell growth, and proliferation, while the general (Carr et al., 2010) and the alanine, serine, cysteine-preferring
controlled non-repressed kinase 2 (GCN2) senses amino acid transporter 2 (ASCT2; Slc1a5) (Nakaya et al., 2014). ASCT2
starvation by detecting uncharged tRNA. The precise mecha- disruption inhibits Th1 and Th17 differentiation, though prolifera-
nisms of amino acid sensing by these molecules have been exten- tion and IL-2 production are normal (Nakaya et al., 2014). The
sively reviewed elsewhere (Bar-Peled et al., 2013; Kedersha et al., increased glycolysis and mitochondrial metabolism necessary to
2002; Saxton and Sabatini, 2017; Taniuchi et al., 2016). mTORC1 support T cell differentiation is also impaired in Asct2 / CD4+
licenses immune cell activation only when enough resources are T cells, as they have decreased glucose uptake, lactate produc-
present. Active mTORC1 promotes the differentiation of CD8+ tion, and oxygen consumption. Glutamine addition rescues these
cytotoxic T cells (CTLs) (Pollizzi et al., 2015; Rao et al., 2010), con- effects, though other amino acids transported by ASCT2 could
trols Tmem cell formation (Araki et al., 2009a; Pearce et al., 2009), theoretically also contribute to the phenotype.
and stimulates helper T (Th)1 and Th17 differentiation while re- While glutamine supports both Th1 and Th17 cell differentia-
straining regulatory T (Treg) generation (Delgoffe et al., 2011). In tion, glutamine degradation by glutaminolysis may be more crit-
macrophages, pharmacologically activating GCN2 and the amino ical specifically for Th17 cells, while other downstream effects of
acid starvation response dampens IL-1b production (Battu et al., glutamine may influence Th1 cell differentiation (Johnson et al.,
2018), and inhibits inflammasome-mediated gut inflammation 2018). This is illustrated in mice lacking glutaminase 1 (Gls1)
(Ravindran et al., 2016). Upon activation, both innate and adaptive (Kono et al., 2018), which metabolizes glutamine to glutamate.
immune cells must sense their amino acid supplies in order to In cells from wild-type mice cultured in Th17-polarizing condi-
engage the new biosynthetic programs that accompany this acti- tions, the inducible cAMP early repressor (ICER) isoform of the
vation, and mTORC1 and GCN2 are central regulators of amino cAMP response element modulator transcription factor binds
acid usage in this context. to the Il17a promoter and drives Th17 cell generation. ICER rein-
forces this differentiation by also binding to the Gls1 promoter,
Amino Acids Support Immune Cell Metabolic increasing Gls1 levels and consequent glutamine utilization
Reprogramming (Kono et al., 2018). Gls1 deficiency impairs Th17 cell differentia-
Immune cell activation by receptor ligation and cytokine tion by limiting aKG supply. aKG is a cofactor for DNA and his-
signaling induces drastic changes in transcription and transla- tone demethylases, which modify chromatin methylation to
tion, for cytokine and effector molecule production, as well as impact gene expression (Xiao et al., 2012). Gls1 disruption
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Figure 1. Amino Acids Support Glycolysis
and Mitochondrial Metabolism
Amino acids influence cellular metabolism by
contributing to glycolysis, and the tricarboxylic
acid (TCA) cycle and OXPHOS in the mitochondria.
Leucine and isoleucine increase translocation of
the glucose transporters GLUT1 and GLUT4 to the
cell surface in muscle cells and provide CoA in-
termediates to the TCA cycle, as does valine.
Serine activates the key glycolytic enzyme PKM2
in macrophages and can increase translation of
mitochondrial proteins in T cells, including those of
the electron transport chain. PKM2 activity is also
needed for T cell differentiation and cytokine pro-
duction. While pyruvate can be used to make
alanine, activated T cells decrease alanine syn-
thesis from pyruvate, in order to preserve pyruvate
metabolism to acetyl-CoA for TCA cycle activity. In
macrophages and plasma cells, glutamine sup-
plies the TCA cycle by anaplerosis to a-ketoglu-
tarate, via glutamate.
tion in ASCT2-deficient mice in response

to Bordetella pertussis is normal (Masle-
Farquhar et al., 2017).
Anaplerosis is a mechanism of replen-
ishing TCA cycle intermediates that have
been removed for biosynthetic reactions.
Glutamine anaplerosis to aKG is
increased in pro-inflammatory M1-like
macrophages, and, due to a break in the
TCA cycle, causes a build-up of succi-
nate, which drives IL-1b production. Nitric
oxide (NO)-mediated inhibition of pyru-
restrains mTORC1 and IL-2 signaling, and consequent T cell dif- vate dehydrogenase and aconitase-2 limits entry of metabolites
ferentiation, by altering the effects of aKG on chromatin (John- into the TCA cycle, promoting this glutamine anaplerosis to aKG
son et al., 2018). At the same time, Gls1 deficiency increases in inflammatory macrophages (Palmieri et al., 2020). Glutamine is
the transcription factor T-bet to promote differentiation and needed to support LPS induction of IL-1 production by macro-
effector function of Th1 and CD8+ CTLs. Restricting glutaminol- phages (Wallace and Keast, 1992), though it does not appear
ysis may increase glutamine availability for other processes, or to be required for M1-like macrophage development. Glutamine
may limit aKG to generate an epigenetic landscape supporting flux into the TCA cycle underlies M2-like macrophage polariza-
T-bet-mediated Th1 cell differentiation and function. Therapeuti- tion by IL-4 (Jha et al., 2015; Liu et al., 2017). Plasma cells also
cally, Gls1 inhibition ameliorates hyperinflammation in experi- use glutamine for anaplerotic glutamate and aspartate replace-
mental autoimmune encephalomyelitis (EAE) (Kono et al., 2018) ment (Lam et al., 2018). In contrast, activated NK cells use
and in a model of rheumatoid arthritis (Takahashi et al., 2017). some glutamine to replenish TCA cycle intermediates and in-
Downstream of glutamine uptake, glutamine degradation by glu- crease OXPHOS, but the glucose-supplied citrate-malate shut-
taminolysis is a major catabolic pathway supporting the function tle has a bigger role in driving TCA cycle activity in these cells
of specific T cell subsets. (Loftus et al., 2018). NKT cells, a cell type that shares features
Glutamine metabolism differs between different immune cell of both innate and adaptive immune cells and express a highly
types. IL-2/IL-12-induced Myc-dependent natural killer (NK) restricted TCR repertoire, need glutamine for survival and prolif-
cell activation requires Slc7a5-mediated glutamine uptake (Lof- eration, though how this glutamine is used is unknown (Kumar
tus et al., 2018). Glutamine acquisition, not degradation, is et al., 2019). Clearly, many immune cells increase glutamine up-
important in this context, as glutamine withdrawal, but not gluta- take. Glutaminolysis supports the function of some of these im-
minolysis blockade, inhibits NK cell activation. NK cells could mune cells, while others funnel glutamine into other metabolic
instead use glutamine for glutathione or hexosamine synthesis. pathways. Improved understanding of glutamine utilization in
In contrast, glutaminolysis supports antibody production by acti- different cell types will enable more specific targeting of gluta-
vated B cells. Overexpression of the let-7adf microRNA cluster mine metabolism in a therapeutic setting.
represses ASCT2 and Gls1 expression in activated B cells, Branched-Chain Amino Acids Provide TCA Cycle
decreasing IgM and IgG production (Jiang et al., 2018). Gls1 in- Intermediates
hibition may be the important event here, as B cells lacking Glutamine is not the only amino acid that supports metabolic re-
ASCT2 develop and proliferate normally, and antibody produc- programming by supplying TCA cycle metabolites. The

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Box 1. How Metabolism Links to Immune Cell Activation and Function
Immune cell activation induces metabolic reprogramming compared to unstimulated or naive immune cells. Pro-inflammatory M1-
like macrophages dampen OXPHOS and rely on glycolysis, the pentose phosphate pathway, and fatty acid synthesis (Krawczyk
et al., 2010; Newsholme et al., 1986; Tannahill et al., 2013). M2-like macrophages, which promote anti-helminth responses and
resolve inflammation, rely more on the TCA cycle to support OXPHOS, as well as FAO (Huang et al., 2014; Vats et al., 2006).
DCs also upregulate glycolysis upon activation (Wculek et al., 2019). Upon TCR stimulation, naive T cells proliferate and differen-
tiate into different subtypes. Glycolysis and OXPHOS drive proliferation and cytokine production by Teff cells (Chang et al., 2013;
Sena and Chandel, 2012), while CD8+ Tmem cell generation and survival depend on OXPHOS and FAO (Pearce et al., 2009; van der
Windt et al., 2012). Naive and regulatory CD4+ T cells engage FAO (Beier et al., 2015), while glycolysis predominates in Th1, Th2,
and Th17 effector CD4+ T cells (Gerriets et al., 2015). B cell receptor (BCR) stimulation of naive B cells increases glycolysis and
OXPHOS (Akkaya et al., 2018), while antibody-secreting cells rely on sustained glutamine consumption (Garcia-Manteiga et al.,
2011). These pathways are interlinked and co-regulated, and increased use of a particular pathway does not mean that other path-
ways are completely abandoned. Acquisition of energy and use of metabolites is fundamental to cell function, and immune cells
can quickly switch between metabolic pathways to support various activities. Nutrient supply and transporter expression dictate
metabolic pathway utilization, underlying how varying microenvironments and signals can alter immune cell function.
branched-chain amino acids (BCAAs) leucine, isoleucine, and take, and pyruvate-dependent mitochondrial respiration are bet-
valine provide the coenzyme A (CoA) derivatives acetyl-CoA ter able to distinguish between long- and short-lived plasma cells
and succinyl-CoA, which enter the TCA cycle (Neinast et al., (Lam et al., 2016, 2018). Understanding plasma cell longevity
2019). Leucine transamination also produces glutamate, which and persistence is beneficial in terms of generating long-lived im-
feeds the TCA cycle via aKG. Acetyl-CoA condenses with oxalo- mune responses after vaccination (White et al., 2015). Given
acetate to form the TCA intermediate citrate. Similar to glutamine these clear differences in metabolic signatures, manipulation of
transporters, large neutral amino acid transporters are increased plasma cell metabolism is an intriguing potential method to in-
upon immune cell activation. L-type amino acid transporter 1 crease the duration of humoral immunity to pathogens.
(LAT1; Slc7a5) is an excellent example of how an amino acid Branched-chain amino acid aminotransferase (BCAT1), the
transporter can link pathogen infection to the immune response. first enzyme of BCAA catabolism, transaminates BCAAs to
In vivo listeria infection increases Slc7a5 expression on T cells, branched-chain a-keto acids, which are decarboxylated to
and IL-2 sustains this expression, maintaining continuous form CoA derivatives (Brosnan and Brosnan, 2006). BCAT1 inhi-
BCAA supply to the activated T cells (Sinclair et al., 2013). TCR bition restrains both glycolysis and oxygen consumption, and
stimulation of human T cells upregulates Slc7a5 (Hayashi et al., limits production of itaconate (Papathanassiu et al., 2017), an
2013), as does IL-18 stimulation of NK cells (Almutairi et al., anti-inflammatory metabolite (Mills et al., 2018). Older work
2019). Slc7a5 inhibition dampens IFN-g and IL-17 production showed that mice fed diets lacking BCAAs generate defective
(Hayashi et al., 2013), and Th1 and Th17 cell development, but antibody and cytotoxic T cell responses in response to Salmo-
Treg cells develop normally (Sinclair et al., 2013). Slc7a5-deficient nella typhimurium (Petro and Bhattacharjee, 1981) or mammary
T cells cannot undergo the mTORC1- and Myc-dependent in- adenocarcinoma (Jose and Good, 1973), while BCAA supple-
crease in glycolysis necessary for activation (Sinclair et al., mentation enhanced liver CD8+ T cell activity in a murine model
2013). Strikingly, knockout of Slc7a5 alone largely phenocopies of liver cirrhosis (Tsukishiro et al., 2000), and increased lympho-
the effect of Myc deficiency on the activated CD4+ T cell prote- cyte numbers and responses to skin antigens in patients with
ome, and impairs T cell growth (Marchingo et al., 2020). The fact post-operative trauma or sepsis (Cerra et al., 1984). Valine
that loss of a single transporter has effects as drastic as knocking boosts DC IL-12 production in cirrhotic patients (Kakazu et al.,
out such a central regulator as Myc illustrates the importance of 2007). BCAAs could also support metabolic reprogramming of
amino acid transport and acquisition for T cell function. immune cells by stimulating glucose uptake to promote glycol-
Slc7a5 also underlies macrophage metabolic rewiring. LPS in- ysis. In rat muscle cells, leucine and isoleucine increase translo-
creases BCAA transporter expression in macrophages, and cation of the glucose transporters (GLUTs) GLUT1 and GLUT4 to
macrophages lacking leucine transport via Slc7a5 have reduced the cell surface to increase glucose uptake (Nishitani et al.,
glycolysis and IL-1b production (Yoon et al., 2018). CD98 is 2005), in a process that may depend on PI3K and protein kinase
needed for Foxp3+ Treg (Ikeda et al., 2017) formation, prolifera- C (Doi et al., 2005a). Leucine-supplied acetyl-CoA could also
tion of T and B cells (Cantor et al., 2009, 2011), and NK cell cyto- acetylate and activate mTORC1 (Son et al., 2019), further rein-
kine production (Jensen et al., 2017). CD98 expression is high in forcing enhanced glycolysis.
antibody-secreting plasma cells, and its absence impairs anti- Serine Promotes Glycolysis and Mitochondrial
body production. Cell surface expression of CD98 correlates Metabolism
with plasma cell longevity (Shi et al., 2015; Tellier et al., 2016), Serine also increases glycolytic flux. It ligates and allosterically
and plasma cells with high surface levels of CD98 secrete activates pyruvate kinase M2 (PKM2) (Chaneton et al., 2012),
more antibodies than short-lived plasma cells with low surface which converts phosphoenolpyruvate to pyruvate in the last
CD98 expression. Interestingly, these populations with very step of glycolysis. LPS induces PKM2 in macrophages to drive
different longevities have similar transcriptional profiles, but the metabolic switch toward glycolysis and IL-1b induction
metabolic parameters such as CD98 expression, glucose up- (Palsson-McDermott et al., 2015). TCR stimulation of CD4+

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T cells increases nuclear translocation of PKM2 (Wang et al., cytokine production (Bulua et al., 2011) and bacterial killing
2011), which increases glycolysis to support Th1 and Th17 cell (West et al., 2011). ROS can activate the nuclear factor of acti-
generation, and tumor necrosis factor (TNF) and IL-17 produc- vated T cells (NFAT), a T cell-specific transcription factor that
tion. Inhibition of PKM2 nuclear translocation by inducing its tet- induces IL-2 production and cell-cycle engagement, increasing
ramerization limits Th1 and Th17 generation and cytokine pro- T cell proliferation (Sena et al., 2013). Elevated ROS drive cal-
duction, and inhibits the development of EAE, a murine model cium signaling, promoting nuclear translocation of NFAT to in-
of neural inflammation including multiple sclerosis (Angiari crease transcription of target genes, including Myc, needed for
et al., 2020). Serine limitation also inhibits PKM2 to decrease T cell activation and metabolic reprogramming toward increased
excessive macrophage activation in atherosclerosis (Shirai glycolysis and glutaminolysis. The balance of ROS is critical, as
et al., 2016), and inhibition of serine synthesis decreases IL-1b an excess of these free radicals can cause cell damage and sub-
and TNF production in LPS-induced endotoxemia (Rodriguez sequent pathology (Chouchani et al., 2014; Sena and Chandel,
et al., 2019). 2012). BCR stimulation of naive B cells also induces massive
Serine also supports mitochondrial metabolism. The catabolic ROS production and calcium-induced mitochondrial dysfunc-
enzyme serine hydroxymethyltransferase (Shmt2) is needed for tion. This causes activation-induced cell death unless the B
mitochondrial translation and respiratory activity (Minton et al., cell also receives costimulatory signals such as TLR or CD40
2018), and Shmt2-deficient mice have respiratory defects (Tani engagement, which prevent the mitochondrial dysfunction
et al., 2018). This effect depends on generation of one-carbon through an uncharacterized mechanism (Akkaya et al., 2018).
(1-C) units from serine (Stover and Schirch, 1990). 1-C units Thus, cells have multiple antioxidant mechanisms to control
are used for processes including nucleotide synthesis and ROS levels, and amino acids are crucial for maintaining these de-
methionine recycling, and enzymes of mitochondrial 1-C meta- fenses and redox balance (Figure 2). Major cellular antioxidants
bolism are upregulated in proliferative tissues (Mejia and MacK- include glutathione, thioredoxins, glutaredoxins, superoxide dis-
enzie, 1985; Nilsson et al., 2014). Mitochondrial translation mutase, and catalase (Sies et al., 2017; Zhang and Hannink,
initiation depends on the modified tRNA, N-formylmethionine- 2003). For example, glutathione peroxidase 4 prevents lipid
tRNAMet (fMet-tRNAMet), formed from serine via Shmt2. 1-C oxidation to support T cell survival and activation (Matsushita
unit supplementation rescues defects in respiration and mito- et al., 2015). Immune cells have harnessed these antioxidant
chondrial translation in Shmt2-deficient Jurkat cells. This systems to modulate activation and cytokine production.
pathway seems to be especially important in low-glucose condi- Glutathione Is Needed for T Cell and Macrophage
tions that induce cells to increase mitochondrial metabolism in a Function
compensatory manner, so it may also be important for immune Glutathione is a small molecule composed of glycine, glutamate,
cells that switch from glycolytic to mitochondrial metabolism. and cysteine. Thus, supply of these amino acids dictates gluta-
However, even T cells with sufficient glucose to support thione levels. The reduced form of glutathione (GSH) is oxidized
increased glycolysis, OXPHOS, and effector function rely on 1- to form a disulfide bridge with another GSH molecule, becoming
C metabolism downstream of serine (Ma et al., 2017). Methylene oxidized glutathione (GSSG). GSSG is recycled to GSH by gluta-
tetrahydrofolate dehydrogenase 2 catalyzes intermediate steps thione reductase (GSR), maintaining an intracellular GSH pool
in mitochondrial fMet-tRNAMet formation, generating NADH. In that detoxifies ROS (Lu, 2009). Increased ROS production
pancreatic tissue with impaired mitochondrial respiration, this upon immune cell activation increases demand for GSH, and
NADH can accumulate to toxic levels, inhibiting cell growth such increased GSH synthesis requires a supply of its compo-
(Yang et al., 2020). It would be intriguing to investigate whether nent amino acids. GSH levels are indeed increased upon T cell
cells that switch away from mitochondrial metabolism concom- activation (Mak et al., 2017), and de novo GSH synthesis, rather
itantly decrease this serine catabolism to avoid such toxicity and than recycling from GSSG, is important for T cell differentiation
permit continued growth. and function (Lian et al., 2018). Deficiency of the GSH synthetic
While other amino acids can fuel glycolysis and the TCA cycle, enzyme glutamate cysteine ligase (GCLC), but not that of the
sometimes T cells do not use them for these pathways. Extracel- GSH recycling enzyme GSR, reduces activated T cell viability,
lular alanine is necessary for early activation of T cells (Ron-Harel proliferation, and expression of the activation marker CD25
et al., 2019). While alanine can be metabolized to pyruvate, the due to aberrant ROS balance (Lian et al., 2018). Glutamine sup-
end product of glycolysis, it is not used for this purpose in acti- plies glutamate for such de novo GSH synthesis, and Gls1 inhi-
vated T cells, and is instead used for protein synthesis. Further, bition antagonizes T cell differentiation and function. Glutathione
although alanine can be synthesized from glucose via alanine also impacts the increased glycolysis and glutamine utilization
aminotransferase, expression of this enzyme is low in T cells underlying T cell activation. Conditional Gclc deletion abolishes
early after activation, which instead take up extracellular alanine mTORC1 activation, the nuclear accumulation of NFAT, and
via SNAT1 (Matheson et al., 2015). This preserves pyruvate for the Myc-dependent switch toward glycolysis and glutaminolysis
acetyl-CoA production, TCA cycle activity, and OXPHOS, while in activated CD4+ and CD8+ T cells (Mak et al., 2017). These cells
the extracellular alanine is used for protein synthesis. initially activate normally but cannot meet the metabolic de-
mands for expansion and fail to proliferate (Mak et al., 2017). In
Amino Acids Control Sulfur and Redox Metabolism contrast, Gclc-deficient Treg cells increase mTOR activity, which
Immune cell activation frequently depends on increased ROS inhibits Foxp3 expression and Treg suppressive function (Kurnia-
ski et al., 2012; Sena et al., 2013), which can
production (Kamin wan et al., 2020). Gclc-deficient Treg cells increase serine import
be generated by the mitochondria and cytoplasmic NADPH ox- and synthesis, possibly in an attempt to generate glycine for
idases. LPS induces ROS production in macrophages to drive GSH, via Shmt enzymes. In this context of impaired GSH

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Figure 2. Sulfurous Amino Acids Maintain
Redox Balance and Drive Protein Synthesis
Cysteine, glutamine, and glycine make the anti-
oxidant glutathione (GSH), which is oxidized to
GSSG to detoxify reactive oxygen and maintain
intracellular redox balance. T cells increase GSH
synthesis upon activation, and B cells and mac-
rophages also need GSH to regulate redox status
after ROS production upon activation. DCs can aid
this process by providing cysteine to other immune
cells. Methionine and serine can be metabolized to
cysteine, with methionine also generating S-ad-
enosylmethionine (SAM), which provides methyl
groups to modify immune effector proteins and
nucleic acids, facilitating cytokine gene expression
in T cells and macrophages, and both innate and
adaptive immune memory. Cysteine is a sulfur
donor for processes including tRNA thiolation,
which aids translation, and iron sulfur (FeS) cluster
synthesis. FeS clusters are key for the activity of a
variety of enzymes, including components of the
electron transport chain.
DCs and CD4+ Teff cells depletes extra-

cellular cysteine, possibly explaining
some of the suppressive effect of Treg
cells on Teff cell proliferation. Thus, innate
immune cells modulate amino acids in or-
der to regulate adaptive immune cell
function.
Cysteine Supports Sulfur-
Dependent Metabolism
Cysteine is a key amino acid for GSH
function, as it supplies the sulfur neces-
sary for formation of the disulfide bridge
synthesis, serine instead activates mTOR, which inhibits Foxp3 in GSSG, but its roles extend beyond GSH synthesis. Cysteine
expression. Serine limitation restores Foxp3 expression and predominantly exists in its oxidized form, cystine, in the oxidative
Treg suppressive activity, decreasing lethal auto-inflammation extracellular environment. Cystine uptake is needed for T cell
in vivo. So one function of GSH in Treg cells is to restrict serine activation (Srivastava et al., 2010), proliferation (Levring et al.,
metabolism, thereby maintaining their suppressive function. 2012), and DNA synthesis (Levring et al., 2015). Blockade of
Macrophages also use serine to generate glycine for GSH, cystine uptake by T cells is protective against EAE (Evonuk
needed for LPS-induced IL-1b mRNA expression (Rodriguez et al., 2015). Similar to B cells, resting T cells do not express
et al., 2019). This serine-glycine-GSH regulatory loop illustrates xCT, but activated CD4+ and CD8+ human T cells increase
how amino acids and small peptides regulate the metabolism xCT to promote cystine uptake (Siska et al., 2016). Blockade of
of other amino acids. this antiporter in monocytes inhibits their differentiation into
Cysteine/cystine import supports immune cell function, at DCs in response to IL-4 and granulocyte-macrophage colony-
least in part by facilitating GSH synthesis. Resting B cells do stimulating factor, and its inhibition in mature DCs impairs anti-
not express xCT (Slc7a11) but, upon activation, increase xCT gen presentation to CD4+ T cells, as well as cross-presentation
expression and cystine import, possibly to produce GSH to to CD8+ T cells (D’Angelo et al., 2010).
counter the ROS production that would otherwise cause activa- Only two of the proteinogenic amino acids contain sulfur, and
tion-induced cell death (Vené et al., 2010). LPS activation of DCs they are intimately related. Methionine transulfuration to cysteine
increases system xc cystine-glutamate antiporter activity maintains cysteine-dependent processes when extracellular
(D’Angelo et al., 2010), which may be needed to increase GSH cysteine is in limited supply. Via S-adenosylmethionine (SAM)
synthesis to counter the increased ROS production upon activa- and S-adenosylhomocysteine (SAH), methionine can be used
tion. DCs can also export GSH to shape the extracellular redox to produce homocysteine, which forms cystathionine when
environment, particularly around the immune synapse between combined with serine by cystathionine-b-synthase (Stipanuk,
DCs and T cells. This GSH is broken down to cysteine, which de- 1986). This in turn can be metabolized by cystathionine-g-lyase
creases extracellular redox potential and promotes CD4+ Teff cell to form cysteine. Cysteine limitation induces expression of these
proliferation, possibly as CD4+ T eff cells acquire this cysteine for transulfuration enzymes (Zhu et al., 2019). This process is known
GSH production and consequent proliferation (Yan et al., 2009). to occur in the liver and has now been demonstrated in cancer
It alters the redox status of proteins on the T cell surface, with as cells (Zhu et al., 2019), though it has not yet been investigated
yet unknown consequences. Further, co-culture of Treg cells with in an immune cell context.

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Figure 3. Amino Acids Influence Cell
Function by Supplying Intermediates for
Protein and Nucleotide Modifications
Amino acids provide a variety of functional groups
that can be conjugated to intracellular targets.
Methionine, arginine, glutamine, and the
branched-chain amino acids provide in-
termediates for post-translational modifications
(PTMs) of proteins. Such PTMs can alter the ac-
tivity of metabolic pathways and immune cell
function by changing the activity of target proteins.
Many amino acids have not yet been investigated
in this context but are likely to provide in-
termediates that can modify proteins and thus
modulate cellular function.
for translation and growth. During sulfur

limitation, i.e., methionine and cysteine
limitation, such tRNA thiolation is
decreased, slowing translation when nu-
trients are limiting (Laxman et al., 2013).
FeS cluster synthesis and tRNA thiolation
have not yet been investigated in immune
cells, but may have a role to play here, as
maintenance of mitochondrial meta-
bolism and increased translation underlie
immune cell activation. It is easy to ima-
gine a situation in which sulfur could
become limiting in T cells and macro-
phages, which increase ROS upon
activation, and consequently induce pro-
duction of antioxidants, including GSH
Sulfur supply from cysteine is also critical for maintaining mito- (Mak et al., 2017). Prioritizing such GSH production could limit
chondrial metabolism via the synthesis of iron-sulfur (FeS) clus- the use of sulfur for translation, and eventually curb immune
ters (Lill, 2009), key components of many enzymes, including cell proliferation and effector function. Such sulfur competition
some electron transport chain (ETC) subunits. The cysteine de- could be exacerbated in sulfur-deficient microenvironments,
sulfurase NFS1 removes sulfur from cysteine for FeS clusters, and could contribute to differences in proliferation in different en-
and cysteine limitation decreases FeS cluster synthesis. Loss vironments; for example, the continued T cell expansion in lymph
of FeS clusters can itself impact metabolic pathways, as the nodes versus decreased proliferation in tissue populations.
FeS cluster-containing enzyme aconitase can no longer metab-
olize citrate, leading to a buildup of this TCA cycle intermediate Amino Acids Support Nucleic Acid and Protein
and its use in fatty acid synthesis (Crooks et al., 2018). Argi- Modification
nine-derived NO destabilizes FeS clusters (Drapier, 1997), Amino Acids Supply Methyl Groups for Methylation
demonstrating a mechanism by which NO may antagonize mito- Besides its contribution to sulfur metabolism, methionine do-
chondrial metabolism in M1-like macrophages. Besides nates methyl groups for methylation of proteins and nucleotides
decreasing mitochondrial metabolism, decreasing FeS cluster to modulate their function (Figures 2 and 3). Histone and DNA
synthesis leads to an excess of free iron, as it is not being methylation can promote or inhibit transcription by altering the
used for these clusters. This can drive ferroptosis, an iron- accessibility of DNA to transcriptional machinery (Allis and Jenu-
dependent form of cell death (Dixon et al., 2012). Cystine-GSH wein, 2016). Both inhibitory (histone H3 lysine 27, H3K27) and
crosstalk regulates amino acid signaling and ferroptosis (Yu activating (H3K4) histone methylation occur upon T cell activa-
and Long, 2016). Indeed, maintaining expression of NFS1 can tion, underlying transcriptional remodeling (Henning et al.,
protect against ferroptosis, as occurs in tumor cells (Alvarez 2018; Sinclair et al., 2019). RNA methylation controls such pro-
et al., 2017). cesses as mRNA binding to translation initiation factors, mRNA
NFS1 also uses the sulfur atom of cysteine to thiolate tRNA, as stability, and splicing (Aregger and Cowling, 2017; Varshney
shown in Saccharomyces cerevisiae (Nakai et al., 2004). Lysine, et al., 2018). Adenosine methylation to control mRNA stability
glutamine, and glutamate tRNAs can be thiolated on the uridine is important for T cell homeostasis, and T cells lacking the N6-
nucleotide in the wobble position (U34), easing translation by methyladenosine methylation (m6A) of RNA do not expand and
aiding tRNA translocation through the ribosome (Phelps et al., differentiate (Li et al., 2017). Methionine supplies methyl groups
2004; Yarian et al., 2002). Genes enriched in lysine, glutamine, by producing SAM, the methyl donor for DNA, RNA, and protein
and glutamate codons occur frequently in proteins important methyltransferases (Lu, 2000), which transfer the methyl group

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Review
from SAM to a substrate, generating SAH and a methylated sub- signaling (Gu et al., 2017). This illustrates how an amino acid
strate (Figure 2). S-adenosylhomocysteine hydrolase then me- metabolite, rather than the amino acid itself, is sensed by
tabolizes SAH to homocysteine (Hcy). Hcy can be used to mTORC1 as a readout of amino acid levels. TCR stimulation pro-
generate cysteine, a process that is increased in activated motes flux through the methionine cycle, demonstrated by
CD4+ T cells (further illustrating the demand for cysteine in acti- increased production of SAH and Hcy, and CD4+ T cells acti-
vated T cells) or can be recycled to methionine. Th17 cells vated in the absence of methionine have proliferation defects,
starved of methionine or subjected to methionine cycle inhibition but normal expression of activation markers, and lower fre-
exhibit reduced H3K4 methylation at the Il17a promoter and quency of IFN-g-producing cells (Sinclair et al., 2019). Methio-
decrease IL-17 production, while methionine-starved Th1 cells nine restriction limits T cell activation by blunting Myc induction,
produce less IFN-g (Roy et al., 2020). Further, dietary methionine which is critical for T cell activation (Wang et al., 2011).
restriction decreases the numbers of IL-17- and IFN-g-produc- Arginine Contributes to Polyamine Metabolism
ing cells in mice with EAE, delaying the onset of disease and Methylation is not the only PTM controlled by amino acid supply
reducing its severity. (Figure 3). Arginine metabolism also leads to structural modifica-
As well as its acute impact on immune cell function, methio- tion of proteins to influence immune cell function (Geiger et al.,
nine status can have longer-lasting effects by epigenetically 2016; Puleston et al., 2019). Arginase I metabolizes arginine to
modifying immune cell memory. Trained immunity is a program ornithine, which feeds polyamine synthesis, including spermi-
of long-term change that occurs in innate immune cells due to dine production. Highlighting the inherent interconnectedness
pathogen exposure, facilitating increased responses upon re- of metabolic pathways, spermidine production also requires
stimulation (Netea et al., 2016). b-glucan training of human pe- SAM. Thus, its synthesis may report that there is adequate
ripheral blood mononuclear cells enhances H3K4 trimethylation nutrient supply to multiple metabolic pathways, and may signal
at the promoters of genes for cytokines and immune signaling that various metabolites and building blocks are present in suffi-
factors, including MyD88, TNF, and IL-6 (Quintin et al., 2012). cient levels to coordinately fuel biosynthesis, and allow prolifer-
This may underlie the boost in cytokine production by these cells ation to progress. Spermidine is used to make the unusual amino
upon re-exposure to Candida albicans. Adaptive immune mem- acid hypusine, which post-translationally modifies only one
ory also relies on histone methylation. Activating histone marks known target, eukaryotic translation initiation factor 5a (eIF5a)
for cytokines (IL-17, IFN-g) and T cell-specific transcription fac- (Park et al., 1981), which drives translation elongation and termi-
tors (T-bet, ROR-g) are enriched in memory CD4+ T cells nation (Saini et al., 2009; Schuller et al., 2017). This hypusination
compared to naive CD4+ T cells, and this poised chromatin state is critical for eIF5a to maintain expression of ETC enzymes and
leads to more rapid induction of these cytokines in memory OXPHOS activity (Puleston et al., 2019), a process that is upre-
T cells upon stimulation (Barski et al., 2017; Durek et al., 2016). gulated in IL-4-stimulated M2 macrophages. Arginase I activity
Similarly, the genome-wide pattern of both stimulatory (H3K4) is in fact a marker of alternative activation, as its activity is highly
and inhibitory (H3K27) methylation in memory CD8+ T cells is induced in M2-like macrophages, but reduced in M1-like macro-
more similar to Teff cells than to naive T cells (Crompton et al., phages, and arginine usage differs markedly in M2- versus M1-
2016; Russ et al., 2014). Genes for proteins underlying CD8+ like macrophages (Rath et al., 2014). Mouse M1-like macro-
memory T cell formation, such as the transcription factor B- phages metabolize arginine via inducible NO synthase (iNOS)
lymphocyte-induced maturation protein (BLIMP)1, and cytotoxic to produce citrulline and NO, which inhibits OXPHOS. As a
effector molecules granzme A and perforin, are hypermethylated consequence, glycolysis increases and supports pro-inflamma-
on histone H3 (Araki et al., 2009b), facilitating increased expres- tory macrophage function, including cytokine production. In M2-
sion of these genes and illustrating how epigenetic marks sup- like macrophages, arginase I metabolizes arginine to ornithine
port memory T cell function. Histone methyltransferases mediate and urea. This use of arginine by macrophages may also limit
histone methylation, using SAM as a methyl donor and produc- arginine to inhibit T cell activation (Pesce et al., 2009; Rodriguez
ing SAH. SAH can act as a competitive inhibitor of SAM, and thus et al., 2004). While arginase I activity is reduced in M1-like
the balance between SAM and SAH, and flux through the methi- macrophages, it is not absent, and ornithine metabolism to poly-
onine cycle, could impact the extent of histone methylation. amines by ornithine decarboxylase (ODC) limits M1-like macro-
Methionine Transport Underlies T Cell Activation phage activation and inflammation during bacterial infection.
Antigen-stimulated T cells increase and sustain methionine ODC deletion increases inflammatory gene expression due to
transport into the cell, which is a rate-limiting step for the supply altered histone methylation and acetylation, and re-addition of
of methyl donors and methylation of targets in activated T cells putrescine reverses these chromatin modifications and avoids
(Sinclair et al., 2019). Expression of methionine transporters is the hyperinflammation caused by ODC deficiency (Hardbower
restricted to activated T cells, so even though naive T cells et al., 2017). Polyamine production supports the function of
have enzymes of methionine metabolism, they cannot transport M2-like macrophages while limiting inflammatory activity of
sufficient methionine into the cell to increase protein synthesis. M1-like macrophages.
Thus, control of cellular methionine levels modulates T cell sta- Macrophages take up arginine from apoptotic cells, which is
tus. Only T cells that can increase methionine transport will metabolized via arginase I and, in a putrescine-dependent
have sufficient methionine to drive methylation, protein synthe- manner, activates the actin regulatory protein Rac1 to enable
sis, and proliferation. Slc7a5 is the main methionine transporter further apoptotic cell internalization, ensuring a supply of metab-
in activated T cells and is important for T cell differentiation (Sin- olites for the macrophage (Yurdagul et al., 2020). Myeloid-
clair et al., 2013, 2019). Methionine supply is sensed by SAM- derived suppressor cells (MDSCs) also increase arginine
TOR, which detects SAM and consequently modulates mTORC1 metabolism via arginase to limit arginine supply to T cells

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Review
(Fletcher et al., 2015), and inhibit NK cell function and IFN-g pro- T cells, which requires an increased supply of UDP-GlcNAc and
duction in a similar manner (Goh et al., 2016; Lamas et al., 2012). therefore increased glutamine uptake. NFAT and c-Myc them-
Arginine-starved NK cells have reduced viability, expression of selves are activated and stabilized by this modification (Golks
NK cell activating receptors NKp46 and NKp30, and diminished et al., 2007; Swamy et al., 2016). OGT is needed for thymic
IFN-g (Lamas et al., 2012). This phenomenon is exploited in T cell self-renewal, and T cell activation and expansion (Swamy
chronic hepatitis C infection by the virus to limit antiviral immune et al., 2016), as well as nascent RNA synthesis, IL-2 production,
responses. Similarly, Th1 polarization promotes arginase I activ- and proliferation in primary human T cells (Lund et al., 2016). O-
ity. Arginine drives a metabolic switch toward oxygen consump- GlcNAcylation of PKM2 promotes its nuclear translocation and
tion and increases spare respiratory capacity in activated T cells, activation of glycolysis in leukemic cells and solid tumors (Wang
and supports CD4+ and CD8+ T cell survival (Geiger et al., 2016). et al., 2017b). Glutamine, as well as glycine and cysteine, can
Polyamine replacement partially rescues the detrimental effects also be used for the S-glutathionylation modification, adding a
of glutamine deprivation on T cell activation, indicating that one glutathione tripeptide to target proteins (Dalle-Donne et al.,
use of glutamine may be its metabolism to arginine for polyamine 2009). It is unknown whether and how this modification functions
synthesis (Wang et al., 2011). Spermidine also has anti-aging in immune cells. Overall, it is clear that TCR stimulation increases
effects (Madeo et al., 2018), which may result from its enhance- UDP-GlcNAc production, which itself requires an increased sup-
ment of immune cell function. Spermidine ameliorates the aging- ply of glutamine, again highlighting transport of glutamine into
induced decline in CD8+ T cell responses to infection and the cell as a point of control of T cell function.
vaccination in an autophagy-dependent manner (Puleston BCAAs Support Acetylation
et al., 2014), and enhances anti-cancer immune responses (Pie- BCAA metabolism provides acetyl-CoA derivatives that can be
trocola et al., 2016). As spermidine levels decrease with age used for acetylation. Leucine-derived acetyl-CoA is used to
(Pucciarelli et al., 2012), dietary supplementation of spermidine acetylate the mTORC1 regulator Raptor via the EP300 acetyl-
(Kiechl et al., 2018) or enhancing spermidine production by intes- transferase in HeLa cells (Son et al., 2019). This activates
tinal microbes (Kibe et al., 2014) may prove beneficial in extend- mTOR, but it remains to be seen how specifically this mechanism
ing lifespan, possibly by maintaining immune cell activity. reports on leucine status, as numerous other inputs can generate
Glutamine Fuels the Hexosamine Biosynthesis Pathway acetyl-CoA. Histone acetylation epigenetically modulates
The hexosamine biosynthesis pathway (HBP) metabolizes gluta- immune cell activation. In general, histone acetylation makes
mine to uridine diphosphate N-acetyl-glucosamine (UDP- chromatin more accessible to transcriptional machinery and is
GlcNAc). Glycosyltransferases use UDP-GlcNAc to glycosylate associated with increased transcription, while histone deacety-
targets including proteins and lipids, to form glycoproteins, lation is associated with repression of transcription (Kouzarides,
proteoglycans, and glycolipids (Lairson et al., 2008). Glutamine 2007). Broad alterations in H3K27 acetylation accompany
starvation or increased glutaminolysis limits glutamine supply to macrophage differentiation, and differences in histone acetyla-
the HBP, thus reducing intracellular UDP-GlcNAc levels, with con- tion contribute to the induction of innate immune tolerance
sequences for T cell function (Grigorian et al., 2007; Lau et al., (decreased responsiveness to restimulation) or training
2007). N-linked glycosylation modulates TCR signaling and inter- (increased responsiveness to restimulation) (Saeed et al.,
action with co-stimulatory molecules such as CD4 and CD8 (De- 2014). Genes involved in glycolysis and mTOR signaling exhibit
motte et al., 2008; Grigorian et al., 2009). Increased N-glycan altered acetylation patterns upon b-glucan training of human pri-
branching of the TCR reduces its activity, inhibiting T cell prolifer- mary monocytes (Cheng et al., 2014). Modulation of HDAC activ-
ation (Demetriou et al., 2001), while N-glycan branching of the ity and promoter acetylation can both positively and negatively
inhibitory molecule cytotoxic T-lymphocyte-associated protein regulate inflammatory gene expression. For example, broad-
(CTLA)4 promotes its retention on the cell surface, compounding spectrum HDAC inhibition limits LPS induction of TNF and IL-6
this anti-growth effect (Chen et al., 2009). Flux through the HBP in macrophages, but increases IFN-b production (Roger et al.,
and N-linked glycosylation also regulate Th17 cell differentiation. 2011). More specific HDAC inhibition reveals that different
High glycolysis and glutaminolysis in Th17 cells restrict HBP activ- HDACs can have opposing effects. HDAC1 and HDAC8 inhibit
ity, limiting N-glycan branching and promoting Th17 cell genera- IFN-b expression, while HDAC6 promotes enhancer activity for
tion (Araujo et al., 2017). Convincingly, addition of glutamine or this cytokine (Nusinzon and Horvath, 2006). H3K9 deacetylation
GlcNAC, or glutaminolysis inhibition, reverses these effects and mediated by HDAC3 limits M2-like macrophage activation by re-
blocks Th17 cell production while driving Treg cell differentiation. pressing IL-4 induction of genes characteristic of M2-like macro-
Antibody-secreting plasma cells also glycosylate antibodies to phages (Mullican et al., 2011).
expand the antibody repertoire, as differential glycosylation of an- Non-histone protein acetylation also impacts immune cell
tibodies changes protein folding and interactions of antibodies function. Activity of the central pro-inflammatory transcription
with Fc receptors (Jennewein and Alter, 2017). It remains un- factor nuclear factor (NF) kB requires its acetylation (Yeung
known whether different plasma cell subsets, or plasma cells in et al., 2004), and NOD-, LRR-, and pyrin domain-containing pro-
different nutrient environments, vary in terms of glutamine uptake tein (NLRP)3 acetylation promotes inflammasome activation (He
and HBP usage, thereby generating different antibodies in a et al., 2020). Acetylation likely underlies the metabolic switches
context-dependent manner. accompanying immune cell activation, as the majority of glyco-
UDP-GlcNAc is also the donor substrate for O-GlcNAc trans- lytic and TCA cycle enzymes can be acetylated, with conse-
ferase (OGT), which catalyzes O-GlcNAcylation, a PTM in which quences for enzymatic function. For example, glyceraldehyde
O-GlcNAc is added to target proteins (Hart et al., 2007). TCR stim- 3-phosphate dehydrogenase acetylation increases its enzy-
ulation and c-Myc activation promote O-GlcNAcylation in CD4+ matic activity in memory CD8+ T cells, boosting glycolysis to

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Figure 4. Do Immune Cells and Tumor Cells
Compete for Amino Acids in the Tumor
Microenvironment?
Within the tumor microenvironment, cancer cells
and immune cells may compete for limited amino
acid resources. Restricting amino acid supply to
some immune cells, such as CD8+ Teff cells, de-
creases their proliferation and effector function,
thereby decreasing anti-tumor immunity. At the
same time, limitation of amino acid supply to
suppressive immune cells, such as Treg cells or
MDSCs, could antagonize their suppression of
effector cell function, thereby boosting anti-tumor
immunity. Increased consumption of amino acids
by tumor cells fuels their proliferation, growth, and
metastasis. Understanding and targeting amino
acid consumption and metabolism by tumor cells
and tumor-associated immune cells is likely to be
beneficial in cancer treatment.
support rapid recall responses and cytokine production (Balmer Aspartate is also needed for nucleotide synthesis. Jurkat cells
et al., 2016). These memory CD8+ T cells increase acetate up- with inhibited ETC activity have decreased aspartate synthesis,
take to expand their acetyl-CoA pool to support this increased which slows proliferation in these cells (Birsoy et al., 2015). The
acetylation, but increased BCAA supply could have the same ef- cytosolic aspartate aminotransferase GOT1 transaminates
fect. Conversely, deacetylation mediated by HDACs can be anti- aspartate to glutamate to transfer reducing equivalents to the
inflammatory, and so limiting supply of BCAAs for acetylation mitochondrial matrix (Toney, 2014) but, upon ETC inhibition,
could achieve similar results. acts in reverse to generate aspartate, to partially compensate
for the loss in mitochondrial aspartate synthesis. This reversal
Amino Acids Are Used for Immune Cell Nucleotide supports proliferation of Jurkat cells with ETC inhibition (Sullivan
Synthesis et al., 2015). It is intriguing to speculate that this process may
Nucleotides are needed to make DNA and RNA during cell divi- occur in cells that intentionally shut down mitochondrial meta-
sion and transcription (Sigoillot et al., 2003). Both purine and py- bolism, for example via intracellular NO production in murine
rimidine nucleotides promote activated T cell progression M1-like macrophages. Mitochondrial metabolism also supports
through the cell cycle (Quéméneur et al., 2003), and Myc in- aspartate synthesis by providing electron acceptors, such as O2.
creases expression of nucleotide synthetic genes (Liu et al., Aspartate synthesis from glutamine requires electron acceptors
2008). Aspartate and glutamine provide carbon skeletons for py- generated by mitochondrial metabolism. In the absence of such
rimidine ring formation, while glycine and tetrahydrofolate (THF) electron acceptors, aspartate synthesis and nucleotide produc-
from serine-glycine metabolism provide carbon for purine syn- tion are decreased (Sullivan et al., 2015).
thesis (Lane and Fan, 2015). Nucleotides can partially rescue
the detrimental effects of glutamine deprivation on T cell activa- Do Immune Cells and Cancer Cells Compete for
tion, indicating that one function of glutamine in immune cell acti- Amino Acids?
vation is provision of nucleotides (Wang et al., 2011). While it is clear that all cells need amino acids for protein synthe-
CD8+ Teff cells increase expression of components of the sis and function, the rapid and dramatic changes in immune cell
serine, glycine, one-carbon (SGOC) network upon activation, status have very particular amino acid requirements. Restricting
and serine limitation impairs T cell proliferation, but not expres- amino acid supply can compromise immune cell function, a sit-
sion of the activation markers CD69, CD25, and CD44, or uation that may arise in a tumorigenic setting to limit anti-tumor
production of IFN-g (Ma et al., 2017). These T cells need extra- immunity. Cancer cells have a high metabolic demand and could
cellular serine to support purine nucleotide production, and compete with immune cells for amino acid resources (Figure 4).
provision of serine-deprived T cells with formate and glycine is Tumor Cells Have Diverse Amino Acid Requirements
sufficient to resume purine biosynthesis and T cell proliferation Tumor cells take up amino acids from the external environment
during serine starvation (Ma et al., 2017). Serine is a major and, like T cells, rely on glutamine uptake (DeBerardinis et al.,
carbon donor to the 1-C pathway. As already mentioned, the 2007). Glycine fuels serine-glycine exchange via Shmt2, and
mitochondrial form of the Shmt enzyme (Shmt2) is critical for glycine consumption correlates with cancer cell proliferation
mitochondrial translation. The cytoplasmic form of this enzyme, (Jain et al., 2012). Increased Shmt2 activity drives serine meta-
Shmt1, supports de novo nucleotide biosynthesis. Glycine has bolism (Yang et al., 2018), which may support cancer cell prolif-
also been reported to have anti-proliferative effects on T cells, eration by supplying nucleotides. Cancer cells indeed increase
by opening a glycine-gated channel in the plasma membrane activity of the SGOC network, in which serine is metabolized to
to reduce intracellular calcium levels, which are necessary for glycine with the concomitant generation of 5, 10-meTHF, a 1-C
T cell activation and proliferation (Stachlewitz et al., 2000). These donor for nucleotide synthesis (Mehrmohamadi et al., 2014). Tu-
differential effects of glycine may be due to the dose of glycine mor-initiating cells have increased methionine cycle activity and
used, or the timing of glycine supplementation. transmethylation rates (Wang et al., 2019b), making these cells

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dependent on extracellular methionine uptake. Inhibition of whether glutamate has a pro- or anti-tumor immunity effect. B
methionine metabolism or limitation of extracellular methionine cells and DCs also express glutamate receptors, allowing for their
enhances cancer cell death. Proline metabolism supports function to be modulated by glutamate. Glutamate signals via the
metastasis formation (Elia et al., 2017), as does pyruvate uptake kainate receptor to increase immunoglobulin production by acti-
by breast cancer cells, which use this metabolite to drive vated B cells (Sturgill et al., 2011). Future research will be needed
collagen hydroxylation to remodel the extracellular matrix, facil- to provide direct evidence for any competition between tumors
itating metastasis (Elia et al., 2019). This collagen modification and immune cells for amino acids, and how this may ultimately
depends on pyruvate metabolism to aKG, which is accompanied modulate protective immunity in cancer.
by alanine secretion, which can drive initial activation of naive Tryptophan and Arginine in Anti-Tumor Immunity
T cells and re-stimulation of Tmem cells (Ron-Harel et al., 2019). Inhibitors of the tryptophan metabolic enzyme indoleamine-2,3-
On the other hand, pyruvate can also increase expression of dioxygenase 1 (IDO-1) have been tested against various types of
the immune checkpoint receptor ligand programmed death cancer, both alone and in combination with checkpoint inhibitors
ligand (PD-L)1 in macrophages (Watanabe et al., 2017). It would (Komiya and Huang, 2018). IDO-1 catabolizes tryptophan to ky-
be intriguing to examine if any of the pyruvate taken up by cancer nurenine, and its expression is increased in both cancer cells and
cells is used to increase PD-L1 expression and dampen the anti- activated immune cells (Yoshida and Hayaishi, 1978), again illus-
tumor response. Increased BCAA catabolism via BCAT1 pro- trating an overlapping requirement between these cell types.
motes glioblastoma growth (Tönjes et al., 2013), possibly by T cells require tryptophan for proliferation and activation (Lee
fueling energy-producing metabolic pathways, yet hepatocellu- et al., 2002; Munn et al., 1999), and using IDO-1 inhibitors to
lar carcinoma progression is associated with decreased target cancer cells may dampen T cell-mediated immunity by
BCAT1-mediated BCAA catabolism (Ericksen et al., 2019). This limiting tryptophan metabolism, which can induce GCN2
preserves BCAAs to activate mTOR. Thus, it will be important signaling. It is thus crucial to target IDO-1 inhibitors specifically
to delineate the amino acid demands of different cancer types. to cancer cells. Overexpression of IDO in tumor cells can also
Altered amino acid supply in the tumor microenvironment could impair T cell responses, possibly by driving tryptophan degrada-
have both pro- and anti-tumor effects, as a result of amino acid tion in cancer cells and limiting tryptophan supply for T cells
metabolism in both tumor cells and various tumor-associated im- (Holmgaard et al., 2013). Increased kynurenine can modulate
mune cells. Deprivation of amino acids in Treg cells, for example, T cell responses, inducing apoptosis (Fallarino et al., 2002),
could abolish their suppressive effect on Teff function, thereby pro- decreasing TCR expression (Fallarino et al., 2006), and promot-
moting anti-cancer activity of Teff cells. TCR stimulation increases ing Treg cell differentiation (Opitz et al., 2011). Kynurenine may
expression of amino acid transporters in Treg cells (Do et al., 2020), outcompete the transport of leucine and methionine by Slc7a5/
and arginine and leucine promote mTORC1 activity in Treg cells, System L in T cells (Sinclair et al., 2018), possibly pushing a
via the small G proteins RagA/B and Rheb1/2 (Shi et al., 2019). more regulatory phenotype by limiting leucine and methionine
This signaling drives suppressive activity of Treg cells, including supply. Kynurenine also inhibits NK cell proliferation (Frumento
inducible T cell costimulator (ICOS) and CTLA4 expression. et al., 2002) and cytokine production (Della Chiesa et al., 2006).
RagA deficiency impairs Treg cell proliferation and accumulation Tumor-associated pDCs accumulate in tumor-draining lymph
in tumors in a B16 melanoma model, allowing expansion of tu- nodes and cause antigen-specific T cell anergy via IDO (Friberg
mor-infiltrating CD8+ T cells with increased granzyme B levels, et al., 2002; Munn et al., 2004). Tumor-associated DCs also
enhancing antitumor immunity (Do et al., 2020). Similarly, different consume arginine and limit its use by T cells, and arginine meta-
B cell subtypes can produce immunogenic and immunosuppres- bolism to spermidine by DCs further pushes IDO expression
sive cytokines and thereby exert either pro- or anti-tumor effects, (Mondanelli et al., 2017). This contrasts with the production of
so amino acid supply to different B cells subsets could either drive spermidine in T cells, which enhances their anti-tumor effect (Pie-
or inhibit anti-tumor responses (Tsou et al., 2016). trocola et al., 2016). Collectively, these actions of DCs limit anti-tu-
It will be important to investigate exactly which cell types take mor immunity by T cells. Inhibition of DC arginase metabolism has
up amino acids in the tumor microenvironment, and whether a greater effect on restoring T cell proliferation in a fibrosarcoma
transporter repertoire and copy number vary, giving particular model than restoration of arginine supply alone (Norian et al.,
cells an advantage in terms of amino acid uptake. Glutamate 2009), indicating that it is not just restriction of arginine supply to
has differential effects on T cells, dependent on transporter T cells that mediates the suppressive effects of DCs. MDSCs
expression. Gls1 is overexpressed in many cancers, which could inhibit CD8+ T cell function by targeting intracellular arginine,
increase glutamate levels. Breast cancer cells secrete glutamate rather than arginine uptake. In a recent report, it was shown that
(Briggs et al., 2016), as do macrophages and DCs (Pacheco MDSCs transfer the glycine-derived metabolite methylglyoxal to
et al., 2007), which often infiltrate tumors. Glutamate inhibits the CD8+ T cells, which forms glycation products with arginine,
xc cystine-glutamate antiporter, which could restrict cystine sup- thereby depleting free intracellular arginine needed for CD8+
ply to T cells, decreasing GSH, ROS detoxification, proliferation, T cell activation (Baumann et al., 2020). Methylglyoxal also op-
and activation. Naive T cells express the glutamate transporter poses the increase in glycolysis supporting CD8+ T cell function.
mGlu5R, which inhibits TCR-mediated activation and proliferation Arginine depletion also dampens IFN-g production and
(Pacheco et al., 2006), but activated T cells express an alternative proliferation of human NK cells (Oberlies et al., 2009).
glutamate transporter, mGlu1R, which counters the anti-prolifera- Tumor-associated macrophages (TAMs) expressing arginase
tive activity of mGlu5R via MEK-ERK1/2 and promotes prolifera- are associated with pro-tumor growth, whereas TAMs with low
tion, IL-2, and IFN-g production (Pacheco et al., 2004, 2006). arginase expression drive tumor regression by promoting
The balance between these two transporters may determine macrophage and NK cell-mediated anti-tumor immunity

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Figure 5. Amino Acids Support Immune Cell Function by Multiple Mechanisms

While amino acids are known to be used for protein synthesis, they are critical for many other cellular processes. They supply intermediates that drive metabolic
rewiring upon immune cell activation, and are used to make antioxidants such as glutathione, maintaining redox balance. They provide methyl and acetyl groups
to epigenetically modify DNA and histones to facilitate specific gene expression programs in immune cells. These intermediates, and others, can also be used to
post-translationally modify proteins and affect their function. Amino acids drive proliferation and growth by fueling nucleotide synthesis and driving translation,
and can also be stored in lysosomes, driving autophagy as a protective mechanism in times of stress.
(Hagemann et al., 2008). Both direct targeting of intracellular transporters on cancer cells can be used to target drugs specif-
arginine metabolism by suppressive immune cells and limitation ically to these cells and may also imply an increased reliance of
of extracellular arginine supply limit anti-tumor T cell immunity, tumor cells on certain amino acids. For example, cancer cells
illustrating how immune cells regulate each other via amino frequently increase expression of Slc1a5, Slc38a2, Slc7a5, and
acid metabolism in a tumor setting. Slc38a5 to increase glutamine uptake, and knockdown or small
Modulation of Cysteine in Cancer Immunotherapy molecular targeting of these factors inhibits tumor cell growth in
Cysteine modulation also controls anti-tumor immunity. Tumor several different preclinical models (Kandasamy et al., 2018).
cells are particularly sensitive to ferroptosis, and CD8+ T cells acti- Small molecule inhibitors of the system xc antiporter compo-
vate ferroptosis in tumors in cancer immunotherapy to drive lipid nent Slc7a11, such as sulfasalazine and erastin, may sensitize
peroxidation and tumor cell death (Wang et al., 2019a). IFN-g tumor cells to oxidative stress (Timmerman et al., 2013). It will
from these T cells decreases Slc3a2 and Slc7a11, components be important to establish selectivity for the transporters of inter-
of the glutamate-cystine antiporter system xc , on tumor cells est, to minimize off-target effects. Amino acid transporters can
(Wang et al., 2019a). This limits cystine uptake by tumor cells, also be hijacked to specifically deliver drugs with amino acid
reducing their capacity to antagonize ferroptosis. Cystine and moieties, or amino acid-like structures, to tumor cells. Nitrogen
cysteine depletion in combination with checkpoint blockade syner- mustards are a class of DNA alkylating agents that kill tumor
gistically increase T cell antitumor immunity. MDSCs may limit cells. Glycine conjugation to a nitrogen mustard compound al-
T cell activation by restricting cysteine availability to T cells (Srivas- lows its uptake by Slc7a5 and selective killing of cancer cells
tava et al., 2010), as may DCs. This effect may be in part due to lim- with high Slc7a5 expression (Hosoya et al., 2008).
itation of GSH synthesis and alteration of extracellular redox status. Cancers exposed to high oxidative stress use amino acids to
Targeting Amino Acid Metabolism for Anti-Cancer produce antioxidant molecules. Lung adenocarcinomas with nu-
Treatment clear factor erythroid 2-related factor (Nrf)2/ Kelch-like ECH-
The dependence of cancer cells on amino acid uptake and meta- associated protein (Keap)1 mutations are highly dependent on
bolism implicates the specific targeting of these processes only in exogenous non-essential amino acids, and diets lacking aspar-
the relevant cell type as a means of cancer treatment. For example, agine or both serine and glycine reduce Keap1 mutant tumor
a prodrug form of a glutamine antagonist, which is preferentially growth in mice (LeBoeuf et al., 2020). This implicates dietary in-
activated by enzymes in the tumor microenvironment, decreases terventions as potential anti-cancer strategies. Acute methionine
glycolysis and OXPHOS in MC38 colon tumors in vivo, yet pro- restriction sensitizes tumor cells to chemotherapy and radiation
motes these parameters in CD8+ tumor-infiltrating lymphocytes treatment in mouse colorectal cancer and sarcoma models, and
(TILs) (Leone et al., 2019). TILs, but not MC38 tumor cells, are such acute methionine limitation was tolerated in mouse and a
able to compensate for decreased glutamine metabolism by small human sample (Gao et al., 2019).
increasing flux of glycolytic metabolites into the TCA cycle. Overall,
this enhances antitumor immunity. Recombinant human arginase Open Questions and Future Directions
1 has been tested in the clinic in an attempt to deplete serum argi- Amino acids influence immune cell function in many more ways
nine supply to tumor cells (Qiu et al., 2015). In this setting, modula- beyond providing material for protein synthesis. Their roles in
tion of arginine supply could also limit anti-tumor T cell activity. central energy metabolism, redox balance, epigenetic modifica-
Differential transporter expression on cancer cells and tumor- tion, and PTMs allow them to modulate immunity via multiple
associated immune cells may facilitate this specific targeting of mechanisms (Figure 5) and, consequently, provide a variety of
amino acid metabolism. Increased expression of particular targets for therapeutic intervention (Box 2).

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Box 2. Therapeutic Implications of Targeting Amino Acid Metabolism
d Amino acid metabolism can be targeted at multiple points, by altering dietary supply, or by modulating transporters, metabolic
enzymes, or storage.
d Inhibitors of the transporters Slc7a5 (Geier et al., 2013) and Slc1a5 (Schulte et al., 2018) antagonize cancer cell growth. This
could spare amino acids to boost immune cell function in a tumor microenvironment, a phenomenon that occurs when gluta-
mine metabolism is specifically blocked in cancer cells (Leone et al., 2019). Transporter inhibition could also target immune
cells to dampen autoimmunity or hyperinflammation.
d Erastin and sulfasalazine inhibit the cystine-glutamate antiporter, which could limit T cell activation in EAE (Evonuk et al., 2015).
d Multiple compounds, including BPTES and CB-839, inhibit glutamine metabolizing enzymes, with potential benefits in EAE
(Kono et al., 2018) and rheumatoid arthritis (Takahashi et al., 2017).
d Blocking GSH synthesis with buthionine sulfoximine could spare its component amino acids for tRNA thiolation and increased
biosynthesis, possibly promoting immune cell proliferation and activation.
d Serine limitation dampens excessive macrophage activation in endotoxemia (Rodriguez et al., 2019), which may aid sepsis
treatment.
d Halofuginone mimics amino acid starvation by pharmacologically activating GCN2. This compound reduces gut inflammation
(Ravindran et al., 2016) and induces autophagy (Chen et al., 2017), which may increase longevity by opposing the age-related
decline in immune cell function.
d Modulating amino acid supply to tumors in combination with checkpoint blockade is a promising anti-cancer strategy, as
observed for cysteine/cystine depletion in a melanoma model (Wang et al., 2019a).
Initial acquisition of amino acids is an early point of control to larly relevant to migratory immune cells, which are likely to
manipulate amino acid metabolism, so much so that viruses experience various microenvironments. Immune cells may
have evolved to target amino acid transporters. HIV targets serine elect not to indiscriminately use available amino acids for pro-
incorporators 3 and 5, and SNAT1 (Slc38a1), on T cells to restrict tein synthesis, but to selectively use them or store them. Lyso-
T cell mitogenesis and antiviral immunity (Matheson et al., 2015). somes could release stored amino acids according to demand
In this respect, amino acid transporters are good possible drug or limit them to induce autophagy as a protective mechanism
targets, and dietary interventions could have similar effects. when nutrients are scarce. Amino acids could also be stored
Both strategies may be beneficial to treat cancer and other pathol- in the form of small peptides such as glutathione, which could
ogies (Box 2). Dietary interventions may avoid undesirable side then be catabolized to release cysteine, glutamate, and
effects associated with pharmacological treatments. Dietary glycine, which can in turn be metabolized to other amino
methionine restriction limits autoimmunity, decreasing Th cell acti- acids. The intracellular amino acid pool is also regulated by
vation and consequently delaying EAE onset and progression transporter expression, but many amino acid transporters
(Roy et al., 2020). This work clearly illustrates that limitation of remain unidentified.
just one nutrient can delay disease. Conversely, amino acid sup- Amino acid-derived PTMs have been investigated in bacte-
plementation could boost anti-pathogen immunity. In particular, a ria, including lysinylation (Kristian et al., 2003) and alanylation
number of clinical trials have been conducted with arginine (Saar-Dover et al., 2012), while arginylation prevents neurode-
supplementation, which enhances NK cell activity and antibody generation in mice (Wang et al., 2017a). However, many
production in an older population vaccinated against Strepto- PTMs have not been investigated in an immune cell, or even
coccus pneumoniae (Moriguti et al., 2005). a mammalian, context. Amino acid supply may dictate the
The relevance of many novel amino acid metabolic pathways to type of PTM formed. For example, the autophagy inhibitor
immune cells is as yet unknown. Diverse immune cells are likely to EP300 can be activated by acetylation or inhibited by spermi-
respond differently to amino acid perturbations, depending on dine. BCAAs provide acetyl groups by generating acetyl-CoA,
whether they express transporters and intracellular metabolic en- while arginine provides spermidine. It would be intriguing to
zymes to process these amino acids. Amino acids outside the investigate whether the balance between BCAAs and arginine
proteinogenic 20 remain to be examined. For example, taurine influences which modification dominates, or if such a phenom-
metabolism is modulated by LPS and IFN-g, and its transporter enon occurs for other PTMs.
is regulated in fetal T cells (Iruloh et al., 2007). Selenocysteine is Overall, targeting immune cell amino acid metabolism is a
an excellent antioxidant and occurs in enzymes including gluta- useful means of augmenting or antagonizing immune re-
thione peroxidases. Selenoprotein deficiency reduces the number sponses, and increased understanding of amino acid meta-
of mature T cells emerging from lymphoid tissues, decreases bolism in immune cells is likely to be of great therapeu-
TCR-induced calcium flux (Verma et al., 2011), and antagonizes tic benefit.
T cell proliferation due to decreased buffering of ROS (Shrimali
et al., 2008), and roles for selenoproteins have been proposed in
ACKNOWLEDGMENTS
allergic airway inflammation (Hoffmann et al., 2007).
Different tissues and niches contain different amino acid We thank Johan Fridén for help with creating the figures. This work was sup-
repertoires (Behringer et al., 2019), a concept that is particu- ported by the Max Planck Society.

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DECLARATION OF INTERESTS ulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite
methylglyoxal. Nat. Immunol. 21, 555–566.
E.L.P. is an SAB member of Immunomet Therapeutics and a founder of Rheos €nert, S., Cieslar-Po-
Behringer, S., Wingert, V., Oria, V., Schumann, A., Gru
Medicines. buda, A., Kölker, S., Lederer, A.K., Jacobsen, D.W., Staerk, J., et al. (2019).
Targeted metabolic profiling of methionine cycle metabolites and redox thiol
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Introduction different ATP-producing pathways, such as glycolysis and mito-

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tion in ASCT2-deficient mice in response

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Box 1. How Metabolism Links to Immune Cell Activation and Function

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DCs and CD4+ Teff cells depletes extra-

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for translation and growth. During sulfur

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Figure 5. Amino Acids Support Immune Cell Function by Multiple Mechanisms

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Box 2. Therapeutic Implications of Targeting Amino Acid Metabolism

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