|

Received: 5 March 2020    Accepted: 10 March 2020

DOI: 10.1111/imr.12858

INTRODUCTION

Immunometabolism: From basic mechanisms to translation

Liza Makowski1  | Mehdi Chaib2 | Jeffrey C. Rathmell3

1
Division of Hematology and Oncology,
Department of Medicine, University of Abstract
Tennessee Health Science Center, Memphis, Immunometabolism has emerged as a major mechanism central to adaptive and in-
Tennessee
2 nate immune regulation. From early observations that inflammatory cytokines were
Department of Pharmaceutical Sciences,
College of Pharmacy, University of induced in obese adipose tissue and that these cytokines contributed to metabolic
Tennessee Health Science Center, Memphis,
disease, it was clear that metabolism and the immunological state are inextricably
Tennessee
3
Department of Pathology, Microbiology,
linked. With a second research wave arising from studies in cancer metabolism to also
and Immunology, Vanderbilt Center for study the intrinsic metabolic pathways of immune cells themselves and how those
Immunobiology, Vanderbilt University
Medical Center, Nashville, Tennessee
pathways influence cell fate and function, immunometabolism is a rapidly maturing
area of research. Several key themes and goals drive the field. There is abundant
Correspondence
Jeffrey C. Rathmell, Department of
evidence that metabolic pathways are closely tied to cell signaling and differentiation
Pathology, Microbiology, and Immunology, which leads different subsets of immune cells to adopt unique metabolic programs
Vanderbilt Center for Immunobiology,
Vanderbilt University Medical Center,
specific to their state and environment. In this way, metabolic signaling drives cell
Nashville, Tennessee TN 37232, USA. fate. It is also apparent that microenvironment greatly influences cell metabolism.
Email: jeff.rathmell@vanderbilt.edu
Immune cells adopt programs specific for the tissues where they infiltrate and reside.
Ultimately, a central goal of the field is to apply immunometabolism findings to the
discovery of novel therapeutic strategies in a wide range of diseases, including can-
cer, autoimmunity, and metabolic syndrome. This review summarizes these facets of
immunometabolism and highlights opportunities for clinical translation.

KEYWORDS

autoimmunity, immune-mediated diseases, infectious diseases, met

1 |  I NTRO D U C TI O N immune suppressive,1 Hotamisligil et al showed in a landmark

Two of the most fundamental features of multicellular life are the
need to effectively distribute nutrients across cells and tissues and
to protect from infection and injury. It is not surprising, therefore,
that links between metabolism and immunity have become apparent
in the past twenty years. Indeed, inflammation is now known to me-
diate many of the pathologies of metabolic syndrome. Conversely,
the metabolic programs of individual cells of the immune system
are under tight control and strongly influence cell function and
differentiation. While malnutrition has long been known as widely
This article introduces a series of reviews covering Immunometabolism: From Basic
Mechanisms to Translation appearing in Volume 295 of Immunological Reviews.
paper in 1993 that adipose tissue produced TNFα in murine mod-
els of obesity and diabetes2 to demonstrate that overnutrition can
promote inflammation. Inflammation drives insulin resistance and
features of diabetes and metabolic syndrome. 3 In addition to met-
abolic tissues regulating immune cells, the metabolism of immune
cells themselves is highly regulated. Warburg described metabolic
changes and aerobic glycolysis in cancer cells early in the 20th cen-
tury4 that are now known to be driven by activated oncogenic sig-
naling pathways. 5 Those same signaling pathways are activated to
promote aerobic glycolysis in stimulated immune cells6-8 and play
key roles to reprogram metabolism from catabolic oxidative path-
ways to anabolic pathways.

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Immunological Reviews. 2020;295:5–14.  |

wileyonlinelibrary.com/journal/imr     5
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6       MAKOWSKI et al.

Each hematopoietic cell type has clearly defined morpho-
logical, expression, and functional characteristics with defined
subtypes that are continuing to be defined as technological ap-
proaches enabling increased sensitivity arise. However, these var-
ied lineages and subsets of each cell type also reside in or travel
to distinct tissue depots which impact function. In this light, it is
not surprising that each population of immune cells has a distinct
metabolism and nutrient usage. First demonstrated by Vats et al9
that macrophage metabolism can influence production of inflam-
matory cytokines as alternatively activated macrophages rely on
a different metabolic program than classically activated macro-
phages, this principle has since been shown in T cells,10 myeloid
derived suppressor cells (MDSCs),11 and dendritic cells (DCs).12
The cytokines and signaling pathways that guide distinct immune
responses also promote these specific programs that support bio-
energetics and biosynthesis. The intersection of metabolism and
immunity at the systemic and cellular levels now forms the rap-
idly evolving field of immunometabolism. The most up-to-date
concepts on the control of cell metabolism through cell intrinsic
signaling mechanisms, the effect of the tissue microenvironment
and nutrient availability on metabolism, and the potential for these
pathways to be targeted or modified in disease are reviewed here
and this volume (Figure 1).
2 | BA S I C M EC H A N I S M S TH AT R EG U L ATE
I M M U N E M E TA B O LI S M
The metabolism of T cells has been an area of intense interest and
has many potential biological and therapeutic implications that illus-
trate the potential of immunometabolism. The majority of research
has focused on uptake and metabolism of glucose, amino acids pri-
marily glutamine, and certain fatty acids, although other metabolites
impact metabolism. When T cells are stimulated through the anti-
gen receptor, CD28 costimulation can increase glucose transporter
GLUT1 expression, glucose uptake and subsequent glycolysis, and
mitochondrial capacity.6,13,14 Conversely, CD28 family inhibitory re-
ceptors cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and
programmed cell death-1 (PD-1) can suppress this metabolic tran-
sition.15,16 T cells that fail to receive CD28 costimulation become
anergic and are metabolically suppressed (ie, have low uptake of
substrates and little mitochondrial metabolism).17 The metabolic

F I G U R E 1   Immunometabolism: From Basic Mechanisms to Translation—Graphical summary of reviews in this collection. This figure
summarizes the series of reviews provided by experts in the field demonstrating the mechanisms of immunometabolism, impacts on certain
tissues such as adipose tissue, and disease states such as inflammation, cancer, and lupus. ATM: adipose tissue macrophage; VAT: visceral
adipose tissue; OXPHOS: oxidative phosphorylation
MAKOWSKI et al.
program of T cells as they differentiate into different subsets and
fates, however, is not shared. While effector T cells induce aerobic
glycolysis, it was shown that memory T cells instead rely on mito-
chondrial metabolism and lipid oxidation18,19 but can rapidly revert
to glycolysis upon restimulation through endoplasmic reticulum-
20
mitochondrial direct interactions that serve as metabolic hubs.
Unlike effector T cell subsets, regulatory T cells (Tregs) do not re-
quire GLUT1 or high levels of glutamine uptake through the amino
acid transporter ASCT221,22 and instead predominantly rely on mi-
10,23-25
tochondrial lipid, pyruvate, and lactate oxidation. Tregs can be
highly glycolytic, but the primary Treg transcription factor, FoxP3,
has also been shown to repress glycolysis and high rates of glucose
metabolism can impair Treg suppressive capacity. 24,26,27 Individual
effector T cell populations also differ, as glutamine metabolism is
essential for CD4 Th17 cells, but effector differentiation of CD4
Th1 and CD8 cytotoxic T cells as well as that of classically activated
M1-like macrophages is restrained by this pathway. 28-30 These dif-
ferences likely reflect varied modes of regulation, roles, and require-
ments of specific tissue sites, and offer distinct opportunities to
selectively modulate immunity (Figure 2).
Multiple signaling mechanisms coordinate after immune cells
are stimulated to mediate metabolic reprogramming and the spe-
cific differences of each cell type and subset. In addition to tran-
scriptional regulation through Myc and hypoxia-inducible factor
(HIF1α) that drive induction of anabolic genes for glycolysis and
8,31,32 33
mitochondrial metabolism in T cells and macrophages, the
mechanistic target of rapamycin (mTOR) pathway plays a critical role
F I G U R E 2   Metabolism regulates immune cell activation. Glycolytic metabolism in immune cells typically leads to activation of an effector
phenotype (eg, effector T, M1-like macrophages, DC, NK, and B cells), whereas oxidative metabolism of substrates such as fatty acids (lipid)
and amino acids including glutamine leads to a regulatory or memory phenotype. Immunometabolism is necessary for not only cellular
energetics, but also contributes to biosynthetic intermediates and signaling
|
      7
in immunometabolism and cell fate. mTOR acts as part of two pro-
tein complexes, with the predominant immunometabolic regulation
occurring through the actions of mTOR complex I (mTORC1) that is
activated downstream of receptor stimulation of phosphatidylinosi-
tol 3-kinase (PI3K) and Akt. As described by Huang et al34 the PI3K/
Akt/mTORC1 pathway serves as a central mechanism to sense and
integrate nutrient availability and signaling to promote T cell metab-
olism and function. mTORC1 is activated at lysosomes through the
combined actions of T cell activation and signaling through PI3K and
Akt that lead to activation of the Rheb GTPase and the coordinated
sensing of essential amino acids through the sestrin/GATOR com-
plex. The lysosomal localization plays a key role in this process as
the amino acid transporter SLC38a9 transports arginine from the
lysosome allow the ability of the sestrin/GATOR complex to sense
leucine and isoleucine and activate mTORC1.35,36 When activated,
mTORC1 regulates a host of cellular functions to promote the transi-
tion from quiescence to anabolic metabolism and proliferation while
suppressing catabolic metabolism. A key target for mTORC1 is the
suppression of the AMP-activated protein kinase (AMPK) by phos-
phorylation of ULK1. AMPK is activated when cells experience en-
ergy stress to maximize oxidative pathways and promote autophagy,
but also can have a role in normal physiology to balance mTORC1 ac-
tivity.37,38 The generally shared aerobic glycolysis processes across
effector T cells may suggest similar dependence on mTORC1. Yet,
it is clear that the mTORC1 pathway has distinct roles in each ef-
fector T cell subset and that a balanced and dynamically regulated
metabolism may be the key to these differential roles. For instance,
 |
8       MAKOWSKI et al.
while CD4 Th1 cells rely on the mTORC1 activator protein Rheb, Th2
has been shown capable of Rheb-independent activation. This may,
however, reflect graded dependencies on the levels of mTORC1 ac-
tivity for each effector T cell subtype. Indeed, Tregs are dependent
on a graded level of mTORC1 activity. In the absence of mTORC1
function, Tregs fail to suppress effector T cells and severe autoim-
munity can ensue.39,40 However, AMPK can promote Treg accumula-
10
tion in vivo and may do so in part by moderating mTORC1 activity,
as the mTORC1 inhibitor rapamycin can promote development of
41
Treg. These findings about regulator and effector T cells demon-
strate that factors that balance and fine-tune mTORC1 signaling
function to integrate microenvironmental nutrients and signals and
are fundamental elements of immunometabolic signaling.
B cell metabolism is also highly regulated and undergoes repro-
gramming as cells progress through development and differentiation.
B cell activation and cytokine stimulation promote glycolysis42,43 much
like T cells, but other pathways can differ. Indeed, flux through the pen-
44
tose phosphate pathway may be limiting in B cells and mitochondrial
activity is tightly regulated that may influence susceptibility to apop-
45
tosis. Germinal centers also provide a dynamic microenvironment
which may be hypoxic to drive glycolysis and alter B cell proliferation
and fate,31 although increased fatty acid metabolism in germinal center
localized B cells has also been reported.46 How these changes relate
to the particular activation and differentiation states of B cells as they
transition through activation, germinal centers, and plasmablast differ-
47
entiation is discussed in detail by Jellusova. Because germinal center
B cells undergo class switch DNA recombination and somatic hyper-
mutation, errors leading to mutations can occur. Hence, many of the
factors that drive B cell activation and metabolism can also lead to ma-
lignant transformation. The mismatch between the oncogene-driven
metabolic demands and the metabolic pathways and flux meant to
support those demands, however, can lead to B cell apoptosis. Thus,
Jellusova et al emphasize that understanding mechanisms that regu-
late B cell metabolism, therefore, informs normal B cell biology as well
as B cell transformation to leukemia and lymphoma. Ultimately, anti-
body-producing B cells have clear metabolic demands to support high
rates of protein synthesis; however, the metabolic requirements of
plasmablasts and long-lived plasma cells remain uncertain.
Innate immune cells also undergo metabolic programming and use
metabolic pathways to control cell fate. Bakker and Pearce provide a
detailed review on the past decade of progress in understanding im-
48
munometabolism with a focus on DC and macrophage metabolism.
Mononuclear phagocytes are important in sampling the environment
and crosstalk with neighboring cells, effectively bridging innate and
adaptive immunity. Appropriate control over cell metabolism is nec-
essary for these interactions and acts to fine-tune inflammatory re-
sponses. After lipopolysaccharide (LPS) stimulation, DCs exhibit a brief
burst of oxidative phosphorylation (OXPHOS) that is downregulated
after several hours to allow cells to engage aerobic glycolysis to fuel
the need for metabolic intermediates. Macrophages have similar met-
abolic reprogramming after danger signal activation such as LPS. Much
of the foundational work for this myeloid immunometabolism arose
from work in macrophages showing two breaks in the tricarboxylic
acid (TCA) cycle after pro-inflammatory stimuli. A main function of in-
hibition of the TCA cycle is that this allows excess citrate to feed into
other anabolic pathways and succinate to promote inflammation.49,50
Also, production of the bioactive metabolite itaconate is stimulated
by pro-inflammatory stimuli. Itaconate plays an anti-microbial role but
more critically it blunts succinate dehydrogenase (SDH) enzymatic
function,51 leading to a build-up of succinate. The block at SDH leads to
the second break in the TCA cycle which promotes mitochondrial ROS
production, HIF1α stabilization, and a continued commitment to gly-
colysis in the activated cell. In addition to inhibition of SDH, itaconate
leads to activation of a potent anti-inflammatory and anti-oxidant tran-
scription factor nuclear factor erythroid 2—related factor 2 (Nrf2).52
There is great interest in itaconate or its derivatives in therapeutic
approaches due to its ability to alkylate cysteines on metabolically
sensitive enzymes. In contrast, alternative M2-like activation of macro-
phages is reliant upon TCA cycle—mediated metabolism of glutamine,
glucose, and fatty acids.9,53 Indeed, transgenic expression of Glut1 in-
creased classically activated macrophage inflammatory function, while
genetic deletion of Glut1 specifically repressed those functions.54,55
Lastly, Bakker and Pearce touch upon the role of mitochondrial
metabolism downstream of a little studied pathway called hypu-
sination through the polyamine spermidine derived from arginine,
an amino acid well studied in macrophage metabolism. 56 Inhibition
of hypusination of eukaryotic initiation factor 5 (eIF5A) led to the
reduction of alternatively activated macrophage markers, TCA
cycle flux, fewer electron transport chain (ETC) components, and
an overall reduced OXPHOS metabolism. Surprisingly, inhibition of
this pathway had no effect on pro-inflammatory macrophage activa-
tion. These disparate findings emphasize the fact that mitochondrial
metabolism in pro-inflammatory macrophages is not to fuel energy
production but to generate metabolic intermediates, whereas in al-
ternatively activated macrophages, OXPHOS is necessary for the
M2 phenotype.
Another innate mechanism of immunometabolic regulation is
through the complement system. The complement system is a pat-
tern recognition receptor (PRR) system that has newly identified
roles to regulate basic T cell metabolism and physiology.57 In addi-
tion to secreted complement that arises from the liver, West et al re-
view recent findings showing that T cells produce small amounts of
intracellular forms of complement.58 C3 and C5 in this setting are
each cleaved to C3a and C3b and C5a and C5b by intracellular pro-
teases. A subsequent set of intracellular receptors then recognize
these ligands that promote glycolysis and lipid oxidation. Indeed,
West et al speculate that complement arose in single-celled organ-
isms as a metabolic and stress-sensing mechanism that subsequently
evolved to recognize and help eliminate pathogens. This intracellular
system may be essential for cell viability, as individuals with comple-
ment deficiency syndromes nevertheless have been shown to retain
expression of intracellular complement components. In addition to
direct actions of complement, the complement regulatory cofactor
CD46 is a human-specific complement receptor which can promote
T cell glycolysis in response to engagement with extracellular com-
plement.57 While the CD46 proximal signals are not certain, the
MAKOWSKI et al.
Notch and PI3K pathways are likely candidates to then promote T
cell glycolysis and inflammation. Importantly, individuals deficient
in CD46 have T cell immunodeficiencies. Overall, complement
has been previously recognized to promote defense from invading
pathogens, but current data support an additional role to maintain
cell survival and tissue homeostasis.
One approach to identify novel immunometabolic regulators is to
take a human genetics strategy. In particular, Mendelian genetic met-
abolic disorders provide insight into genes and pathways essential for
normal metabolic function and influence on immunity, as reviewed in
detail by McGuire.59 While the majority of these diverse disorders
have not presented apparent immunological phenotypes, immune
cells have not yet been extensively explored in these settings. With
clear examples, such as glycogen storage disease-1b that leads to
lymphopenia and diminished ability of T cells to upregulate glycol-
ysis, it is apparent that these human genetic diseases can provide
a wide-ranging opportunity for immunometabolic discovery. Indeed,
screening patients with immune disorders for metabolic phenotypes
recently identified gain-of-function mutations in SDH,60 whereas
polymorphisms in ETC proteins were found to lead to increased in-
cidences of infection.61 In sum, taking this genetic approach based
on human disease coupled with biochemical analyses of T cells may
reveal new immunometabolic regulators and pathways.
3 | I M M U N O M E TA B O LI S M I N TI S S U E S
Much of the work on immunometabolism has been performed by
necessity in vitro and with immune cells from secondary lymphoid
organs, such as spleen and lymph nodes. This is due to technical
challenges caused by the need for large numbers of cells for many
biochemical assays and of the rarity and heterogeneity of specific
immune cell populations in other tissues. These barriers are rapidly
being overcome due to technical advances, and it is clear that while
metabolism based on in vitro assays can teach us a great deal about
immunometabolism, pathways in vivo can be regulated differently.
13
For example, it was recently shown using C-glucose tracing that
effector T cells use glucose differently in vivo, with a greater pro-
portion directed to biosynthetic pathways derived from glycolysis.62
Stable isotope metabolomics and other in vivo and tissue-based as-
says are now increasingly accessible and allow for innovative direc-
tions in our approaches to understand immunometabolism.
One tissue that has been a focus of immunological research is
adipose tissue. A wide range of changes in the adipose tissue—resi-
dent immune cell populations occur with obesity, which can vary by
depot. Macrophages, in particular, change in content and phenotype
from lean to obese to weight-cycled states and influence the devel-
opment of insulin resistance, diabetes, cardiovascular disease, and
cancer. Since back-to-back reports of adipose tissue infiltration by
63-65
macrophages in 2003, the field has shown the importance of
essentially every immune cell in adipose tissue with unique depot
specific differences. Caslin et al66 review the contribution of the pre-
dominant immune cell in fat tissue and adipose tissue macrophages
|
      9
(ATM) where extrinsic effects on local and systemic immunometab-
olism, as well as intrinsic immunometabolism and effects on phe-
notype, are discussed. From the first report of differences in ATM
characteristics between lean and obese,67 the evolution of the ATM
phenotype has varied. In short, in vitro differentiation studies to
generate pro-inflammatory M1-like macrophages vs. anti-inflamma-
tory immunomodulatory M2-like macrophages failed to hold true in
vivo. Advances in flow cytometry, proteomics, metabolomics, and
single cell sequencing of macrophages have shown varied pheno-
types that blend both classical M1-like and alternative M2-like mark-
ers depending on the age of mice, duration on diet, and extent of
obesity or weight loss. The interaction of ATM with oxidized lipids
and other metabolites secreted from adipocytes or varied stromal
cells in adipose impacts inflammation and insulin resistance.68 Thus,
it is increasingly important to assess the metabolic and cellular inter-
actions in the adipose tissue.
In addition to macrophages, a unique visceral fat—specific Treg
population was recently defined that functions to keep this vast
depot of adipose tissue quiescent in terms of inflammation to max-
imally sensitize insulin signaling.69,70 A review by Li and Spallanzani
et al details a critical role of visceral adipose tissue (VAT) mesenchy-
mal stromal cells (VmSCs) in regulating VAT Tregs, local, and systemic
inflammation in obesity.71 VAT Tregs were first identified in 2009
and comprise 40%-80% of CD4+ T cells. VAT Tregs are distinct from
lymphoid tissue—associated Tregs which comprise only 5%-15% of
CD4T cells in that they are derived from the thymus, become more
“VAT like” in the spleen (a poorly understood step), and then seed
VAT early in life. VAT Tregs proliferate and survive in VAT, rather
than result from conversion or recruitment. VAT Tregs are typically
more clonal in a MHCII VAT antigen presenting cell-dependent man-
ner and less heterogeneous than lymphoid-resident Tregs. VAT Tregs
function to improve insulin sensitivity, reduce pro-inflammatory
macrophages, and increase anti-inflammatory macrophages and re-
duce inflammation in adipocytes, among other functions. VAT Tregs
are highly dependent upon the nuclear hormone receptor PPARγ
(distal to TCR signaling) and have a unique transcriptome with many
lipid metabolism genes upregulated compared to non-VAT Tregs.
Tregs in human studies have been shown to be both higher and lower
in obesity, but the nature of these comparative studies is difficult to
interpret without controlled interventions.
VAT Tregs are highly dependent on the IL-33-ST2 axis, which is
typically associated with allergic Th2 response, but is increasingly
appreciated for potent wound healing capacity, promotion of tumor
immunosuppression, and activation of increased metabolism of white
and brown fat, potentially through VmSC-dependent IL-33 produc-
tion.72,73 They describe a fibroblast-like population of mSC with
several phenotypic subsets, three of which produce IL-33 (ie, immu-
nocyte promoting) compared to IL-33-negative adipogenic cells with
markers of pre-adipocytes. High-fat diet feeding transiently reduces
IL-33-producing VmSC cells followed by a reduction in VAT Tregs.
Interestingly, sex hormones appear to regulate subsets of VmSC pop-
ulations and production of IL-33, which could account for differences
in Tregs in basal or obese state between males and females. Like
 |
10       MAKOWSKI et al.
other immune cells in diet-induced obese models, short-term high-
fat diet—induced obesity versus long-term and severe obesity affect
this axis differently. While short-term high-fat diet VmSC-IL33 + cells
are associated with Tregs, this positive association is lost in severe
obesity. Morbidly obese patient adipose tissue contains VmSCs (ie,
are CD9hi) that associate with diabetes, fibrosis, and inflammation.
On the other hand, the CD9lo population that is enriched for PPARγ
and is reduced with diabetes. However, the role of VmSCs in IL-33-
dependent Treg homeostasis in obesity is unclear. Controlled time
course single cell sequencing studies in the future are necessary to
inform on the specifics of cell kinetics that are lacking in single end-
point obesity studies. More research is necessary to understand the
bi-directional crosstalk between stromal cells and Tregs, commonal-
ities between human and mouse, and the kinetics and phenotype of
these cells in obesity and other diseases. Tregs also play key roles to
maintain homeostasis in other peripheral tissues including liver, skin,
and tumors and are reviewed by Wang et al74.
4 |  I M M U N O M E TA B O LI S M I N D I S E A S E
A N D TR A N S L ATI O N
Like activation and differentiation of lymphocytes and myeloid
cells that lead to metabolic reprogramming, viral infections have
been shown to reshape cell metabolism in ways that are central
to the antiviral immune response. Viral infection can alter choles-
terol synthesis,75 and Bahadoran et al focus on influenza-induced
metabolomic reprogramming of immune cells in the lung airway.76
The lung microenvironment comprises barrier cells and mecha-
nisms as well as immune regulatory mechanisms that maintain
homeostasis and defend the body against pathogens. Influenza
infection induces metabolic reprogramming of both immune and
epithelial cell populations to co-opt the host's cells. In epithelial
cells, one example of influenza-induced metabolic reprogramming
is by the induction of an aberrant activation of the PI3K/mTOR/
Akt pathway. Additionally, influenza induces immune cell activa-
tion and differentiation, although the impact of influenza A viral
infection on immune cells is largely uncharacterized. The authors
discussed metabolism in both steady state and upon influenza
viral infection relevant to immune cell populations such as DCs,
macrophages, natural killer (NK) cells, and T cells. For example,
influenza viral infection causes DCs to enter a state of hypergly-
colysis with relatively low oxygen utilization. Macrophages in the
respiratory tract largely play a role in phagocytosing the virus and
infected cells. Yet, M1 macrophages activate a strong antiviral
response including macrophage-derived reactive oxygen species
(ROS) that is deleterious to the host, thus representing potential
targets to reduce disease severity. Influenza infection of T cells
induces a switch from OXPHOS to T effector utilization of glucose
and glutamine. In sum, effector functions of immune cells such as
DCs, NK cells, macrophages, and effector T cells rely upon glycoly-
sis, while T regulatory cells use OXPHOS. Also, systemic glucose or
other microenvironmental foci of influenza infection are discussed
because they shape the immune response. Like tumors, influenza
infection may induce immune suppression and infected epithelial
cells become glucose- and glutamine-dependent. Therefore, a
delicate balance is needed to fuel the immune response without
exacerbating damage to the host.
An ultimate goal of immunometabolism is to exploit the specific
metabolic programs of distinct immune cell populations to treat dis-
ease. Systemic lupus erythematosus (SLE) has been studied exten-
sively in this regard and is reviewed by Teng et al77. The metabolism
of T cells in SLE has been recognized to be altered for nearly twenty
years.78 The wide range of T cell subsets, B cells, and DCs that contrib-
ute to SLE have been shown to have differential metabolic require-
ments. These are impacted by altered systemic nutrition, diet, and cell
intrinsic changes to metabolism. Obesity and metabolic syndrome are
associated with SLE and may contribute to a variety of SLE-associated
pathologies.79 This may occur due to increased nutrient acquisition by
inflammatory cells in settings of hyperglycemia and hyperlipidemia,
but may also be regulated through changes in hormones or adipokines,
such as leptin. A variety of metabolic inhibitors have been tested in
animal models of SLE.80-82 Inhibitors of mTORC1 have shown some
promise, and direct inhibition of glycolysis may also protect from
disease. This effect was strengthened, however, by addition of the
AMPK activator, metformin. A concern in these metabolic inhibitor
treatments has been the potential for widespread toxicity. This con-
cern, however, has not materialized, and treatments have been found
to be remarkably well tolerated. Even blockade of the fundamental
process of glucose uptake was not found to be widely cytotoxic and
provided protection in animal models of SLE.81 Combinations of met-
abolic inhibitors for glycolysis and alternate metabolic pathways now
offer new directions with successful preclinical proof of principle
studies, and it is now important to move to human clinical trials to
combat this auto-immune disease.
Tumor microenvironments can also alter the metabolism of T cells
and macrophages to impair anti-tumor immunity.83 Critically, treat-
ments such as checkpoint blockade therapies act in part through reliev-
ing this metabolic inhibition.15-16,84 Siska et al focus on the “Warburg
effect” which is a key feature of tumor cells and leads to acidification
and the accumulation of lactate in the tumor microenvironment.85 As
a consequence of localized lactic acidosis, immune cell populations
within the tumor microenvironment exert an immunosuppressive
effect and mediate an effective immune escape by tumor cells. The
authors suggested a metabolic-tumor-stroma score (MeTS) as a pre-
dictor of the efficacy of anti-tumor immune responses. MeTS are bro-
ken down into four sub-categories: MeTS 1 which consists of respiring
tumor cells (OXPHOS) with high T cell infiltration (“Hot” tumors);
MeTS 2 with a respiring tumor and glycolytic (Warburg-like) stromal
cells; MeTS 3 with a glycolytic tumor and respiring stromal cells; and
MeTS 4 with a glycolytic tumor and low T cell infiltration (“Cold” tu-
mors). First, the authors provided a historical timeline of the Warburg
effect, and then discussed the Warburg effect in immune cells and
its underlying mechanisms in thorough detail. For example, HIF acti-
vation is not solely dependent on hypoxic conditions, but can also be
achieved under normoxia conditions and the presence of lactate or
MAKOWSKI et al.
pyruvate. The authors also discussed how tumor-derived lactate has
a broad spectrum of effects on tumor growth and metastasis such as
the promotion of cell motility, modulation of tumor-associated fibro-
blasts, impairment of anti-tumor immune cells (NK cells, CD8 T cells,
M1 macrophages, and DCs), and promotion of immunosuppressive
immune cells (MDSC, M2 macrophages, Tregs). Finally, the authors
focused on strategies targeting the Warburg effect for tumor therapy
and immune activation. For example, preclinical and clinical strategies
aimed at targeting LDH-A, LDH-B, MCT1, and MCT4 blocked lactate
secretion which improved anti-tumor immune responses.
Both systemic and local influences can also affect metabolism
and anti-tumor immunity.
Turbitt et al focus on the effect of obesity on T cell metabolism
86
and function in the presence and absence of solid tumors. Obesity
alters not just Treg, but also CD4 and CD8 T cells that play roles in
anti-tumor immunity.87,88 Adipokines, such as leptin, are elevated in
obese individuals and can promote T cell glycolysis and polarization
89
toward an anti-tumor Th1 phenotype. Thus, the authors provide
an explanation of why immune checkpoint blockade provides su-
perior anti-tumor immune responses in both obese preclinical and
clinical models compared to lean models. Leptin reverses metabolic
defects in T cells and increases the expression of PD-1 on their sur-
face. Therefore, immunotherapy such as anti-PD-1 is more efficient
in high-PD-1-expressing T cells that are present in obese individuals.
Moreover, the authors discuss the effects of glycolytic tumors on
the impairment of T cell functions. Highly glycolytic tumor cells in-
duce diminished glucose uptake by T cells and promote immunosup-
pressive myeloid cells such as MDSCs, therefore rendering T cells
less effective. Additionally, the authors discussed obesity-driven
intracellular lipid accumulation in T cells and DCs as a mechanism by
which tumors inhibit anti-tumor immune cell functions. Finally, the
authors highlight novel therapeutic approaches focused on improv-
ing T cell metabolic fitness. Few examples include mTOR inhibition
and the use of anti-diabetic drugs such as metformin in combination
with current immunotherapeutic approaches. These strategies aim
at improving T cell OXPHOS and cytokine production to increase the
efficacy of anti-PD-1 blockade.
Sipe and Chaib et al tackle the role of host-microbial interac-
tions and the impact of microbially derived metabolites on immu-
nometabolism in anti-tumor immunity and other chronic diseases.
Microbes are altered by many interventions and lifestyle factors,
and the metabolic sequelae are just beginning to be uncovered.
While most work on the microbiome has focused on the gut, ex-
tra-intestinal microbes are detected in various tissues, including
tumors, and are susceptible to modification by dietary intake or
changes in body composition such as weight gain or loss. How gut or
extra-intestinal microbes alter their own and the host's metabolism
is actively being researched because the magnitude of our micro-
biome's non-mammalian genetic capacity to generate or modulate
metabolites is vast. The impact of host bile acids and modification
of bile acids by microbes is discussed in detail for cell types includ-
ing tumor-associated macrophages, DCs, MDSC, T cells including
Tregs, Th17, mucosal-associated invariant T (MAIT), NKT, and B
|
      11
cells. Current literature suggests that bile acids or agonism of bile
acid receptors such as FXR or TGR5 in innate and adaptive immune
cells leads to a general downregulation of inflammation in most cell
types. However, microbial modification of bile acids and signaling
through epithelial cells led to activation of bile acid targeted re-
cruitment of NKT cells and improved anti-tumor immunity.90 Thus,
BA composition may influence diseases such as cancer through re-
programming of the immune microenvironment. Interestingly, mi-
crobial dysbiosis and specific microbes including bacteria and fungi
correlate with several cancers, notably tumor subtypes, stage, or
race in breast cancer.91 Furthermore, certain microbes have been
shown to impact response to immune checkpoint blockade in an-
ti-tumor therapy in mice and correlate with therapeutic response in
humans.92-94 Based on these and other related studies, it is possible
that immune perturbations resulting from microbiome composition
and microbially modified metabolites can be targeted for thera-
peutic benefit. There is increasing interest in “bugs as drugs.” The
discovery of novel pathways driven by microbial metabolism that
could be exploited in the treatment of cancer including the clinical
efficacy of immune checkpoint blockade, obesity, and metabolic
syndrome, as well as auto-immune diseases, would be impactful to
understand risk and impact of personalized therapy and improve
therapeutic outcomes.
5 | CO N C LU S I O N A N D PE R S PEC TI V E
The field of immunometabolism has emerged as a major and at-
tractive area of research in immunology and metabolic disease. The
focus on systemic and cellular metabolism and the diversity of meta-
bolic programs of specific cell populations have enhanced our un-
derstanding of both basic biology and metabolic dysfunction, as well
as identified novel targets for anti-inflammatory and anti-tumor im-
mune-based therapies. This issue aims to highlight key areas of cur-
rent research, but many important questions and challenges remain
especially with regard to commonalities or differences between hu-
mans and preclinical models, sex, or race. It is clear that the tissue lo-
cation is critical to immune cell intrinsic metabolism through changes
such as cell-cell crosstalk, viral foci, competition for nutrients, and
extent of hypoxia. Future studies must incorporate the effect of
the microenvironment on immune cell metabolism, and vice versa.
Finding new approaches to understand the diversity of metabolic
programs in specific tissue sites will open new avenues for discovery
and immune modulation. Ultimately, identifying therapeutic targets
is a key goal for the field. While standard-of-care treatments, such
as methotrexate, demonstrate the potential of targeting metabolic
pathways, better understanding of cell and tissue biology will cer-
tainly reveal new targets with increased specificity and reduced tox-
icity. As a rapidly maturing field, immunometabolism is now poised
to move forward to address these needs.
ORCID
Liza Makowski  https://orcid.org/0000-0002-5337-8037
 |
12       MAKOWSKI et al.

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How to cite this article: Makowski L, Chaib M, Rathmell JC.
Immunometabolism: From basic mechanisms to translation.
Immunol Rev. 2020;295:5–14. https://doi.org/10.1111/
imr.12858