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BRIEF REPORT | JUNE 15 2024
Metabolic Plasticity of Regulatory T Cells in Health and Autoimmunity 
Fortunata Carbone; ... et. al
J Immunol (2024) 212 (12): 1859–1866.
https://doi.org/10.4049/jimmunol.2400079

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 The Journal of
Brief Reviews Immunology

Metabolic Plasticity of Regulatory T Cells in Health and

Autoimmunity
Fortunata Carbone,*,† Alessandra Colamatteo,‡ Claudia La Rocca,*
Maria Teresa Lepore,* Claudia Russo,x Giusy De Rosa,‡ Alessandro Matarese,{
Claudio Procaccini,*,†,1 and Giuseppe Matarese*,‡,1

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Immunometabolism has been demonstrated to control qualitative alterations of this cellular subset have been described
immune tolerance and the pathogenic events leading to in several autoimmune diseases. During the last decade, it has
autoimmunity. Compelling experimental evidence also become increasingly clear that intracellular metabolism can
suggests that intracellular metabolic programs influence influence the transcriptional program and function of immune
differentiation, phenotype, proliferation, and effector cells. In particular, glycolysis, mitochondrial respiration, and
functions of anti-inflammatory CD41CD251Foxp31 fatty acid oxidation (FAO) are metabolic pathways specifically
regulatory T (Treg) cells. Indeed, alterations in intracel- used by different immune cell subsets, such as Treg and conven-
lular metabolism associate with quantitative and qualita- tional T (Tconv) cells, and their engagement can change dynam-
tive impairments of Treg cells in several pathological ically during an immune response, depending on the nutrient
conditions. In this review, we summarize the most availability and the signals from the microenvironment (13).
recent advances linking how metabolic pathways control
Treg cell homeostasis and their alterations occurring in Role of intracellular metabolism on Treg cell homeostasis
autoimmunity. Also, we analyze how metabolic manipu- Intracellular regulators of cellular metabolism: mammalian target
lations could be employed to restore Treg cell frequency of rapamycin and AMP-activated protein kinase. The serine-thre-
and function with the aim to create novel therapeutic onine protein kinase mammalian target of rapamycin (mTOR)
opportunities to halt immune-mediated disorders. The plays a central role in the regulation of intracellular metabolism,
Journal of Immunology, 2024, 212: 18591866. as it is able to sense and integrate environmental cues from
nutrients, growth factors, and adipocytokines, consequently
controlling cell growth, proliferation, and differentiation (4, 5).

A
It has been observed that human Treg cells show mTOR hyper-
utoimmune diseases are a group of disorders charac- activation, responsible for their in vitro hyporesponsiveness to
terized by aberrant B and T cell reactivity toward TCR-mediated stimulation; moreover, an oscillatory switch in
self-antigens with loss of immunological tolerance, mTOR kinase activity, achieved by mTOR inhibition through
resulting in tissue damage. In this context, regulatory T (Treg) rapamycin pretreatment, induces Treg cell in vitro expansion
cells, a subset of CD41 T lymphocytes expressing the transcrip- (68). Further supporting the link between metabolism and
tion factor Foxp3 and involved in the inhibition of autoreactive Treg cell homeostasis, the mTOR pathway has been shown to
cell clones, have a crucial role in maintaining peripheral tolerance, be activated also by the adipocytokine leptin, a cytokine-like
thus preventing autoimmunity; indeed, both quantitative and hormone mainly secreted by adipocytes and involved in the

*Laboratorio di Immunologia, Istituto per l’Endocrinologia e l’Oncologia Sperimentale della Salute, Bando Ricerca Finalizzata 2021 (Grant GR-2021-12373337) and
“G. Salvatore,” Consiglio Nazionale delle Ricerche, Napoli, Italy; †Unità di Neuroimmu- Ministero dell’Istruzione, dell’Università e della Ricerca Bando PRIN 2022 (grant n.
nologia, IRCCSFondazione Santa Lucia, Roma, Italy; ‡Treg Cell Lab, Dipartimento 2022YMJXYT) and Bando PRIN 2022 PNRR (Grant P2022CMK43) to F.C.; and by
di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Ministero dell’Istruzione, dell’Università e della Ricerca Bando PRIN 2022 (Grant
“Federico II,” Napoli, Italy; xD.A.I. Medicina di Laboratorio e Trasfusionale, Azienda 20225KH7BZ) to C.L.R. A.M. is the recipient of a fellowship in General Surgery at the
Ospedaliera Universitaria “Federico II,” Napoli, Italy; and {Dipartimento di Medicina
University of Naples “Federico II.”
Clinica e Chirurgia, Università degli Studi di Napoli “Federico II,” Napoli, Italy
1
These authors contributed equally to this work. Address correspondence and reprint requests to Prof. Giuseppe Matarese and Dr. Claudio
Procaccini, Università di Napoli Federico II, Via Sergio Pansini 5, 80131 Napoli, Italy. E-mail
ORCIDs: 0000-0002-9693-3985 (A.C.); 0000-0002-4701-6902 (M.T.L.); 0000-0001- addresses: [email protected] (G.M.) and [email protected] (C.P.)
5869-4445 (C.R.); 0009-0008-7325-1691 (A.M.); 0000-0001-9429-0616 (G.M.).
Abbreviations used in this article: ALA, alpha-lipoic acid; AMPK, AMP-activated protein kinase;
Received for publication February 9, 2024. Accepted for publication April 5, 2024. CaMK4, calcium/calmodulin-dependent protein kinase 4; cKO, conditional knockout; EAE,
This work was supported by Ministero dell’Istruzione, dell’Università e della Ricerca (Bando experimental autoimmune encephalomyelitis; Esrrg, estrogen-related receptor g; FAO, fatty acid
PRIN 2022 Prot. 2022LNHZAP), Ministero dell’Istruzione, dell’Università e della Ricerca oxidation; Foxp3-E2, Foxp3 splicing variant containing exon2; GSH, reduced glutathione;
PNRR Extended Partnership (INF-ACT no. PE00000007 and MNESYS no. PE00000006), iTreg, inducible Treg; MS, multiple sclerosis; mTOR, mammalian target of rapamycin; NRF-2,
and Agenzia Italiana del Farmaco, Ministero della Salute (Bando Ricerca Finalizzata 2019 NF erythroid 2related factor 2; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen
RF-2019-12371111 and Bando PNRR 2022 PNRR-MAD-2022-12375634) to G.M.; species; RRMS, relapsing-remitting MS; SCFA, short-chain fatty acid; SLC7A11, solute carrier
Ministero della Salute (Grant GR-2018-12366154), Fondazione Italiana Sclerosi Multipla
family 7 member 11; SLE, systemic lupus erythematosus; Tconv, conventional T; T1D, type 1
(FISM no. 2022-PRsingle/013), and Ministero dell’Istruzione, dell’Università e della
diabetes; Treg, regulatory T.
Ricerca Bando PRIN 2022 PNRR (Grant P2022T4PKT) to C.P.; Ministero della
Salute, Bando PNRR 2022 (PNRR-MAD-2022-12376126) to C.P. and F.C.; Ministero Copyright © 2024 by The American Association of Immunologists, Inc. 0022-1767/24/$37.50

https://doi.org/10.4049/jimmunol.2400079
1860 BRIEF REVIEWS: TREG CELL METABOLISM IN AUTOIMMUNITY

control of food intake and immune functions. Specifically, lep- uptake, which can fuel fatty acid synthesis, with both glycolytic
tin induces an autocrine feedback loop that, by activating the and oxidative metabolism contributing to Treg cell expansion.
PI3K-Akt-mTOR pathway, increases expression of leptin and Recently, also Treg cell migration has been associated with the
its receptor and directly affects Treg cell proliferation; indeed, induction of glycolytic metabolism. Specifically, Kishore et al. (19)
leptin neutralization, via leptin-specific neutralizing mAbs, have reported that promigratory stimuli, such as engagement of
results in the inhibition of Tconv cells on the one side, and the lymphocyte function-associated Ag 1 (LFA-1) or the costimulatory
induction of Treg cell proliferation on the other side (10). Con- molecule CD28, significantly increased glucose uptake and glyco-
sistently, conditions of metabolic overwork, such as obesity, are lytic rate in Treg cells, promoting their migration (19).
frequently associated with an unbalanced immunotolerance, as Lipid metabolism. Other compelling evidence has indicated that
nutrient overload increases the energy storage in adipose tissue, lipid metabolism is also required for Treg functional competence.
leading to altered leptin secretion and loss of the mTOR fluctu- Indeed, recent reports have shown that inhibiting lipid synthesis
ations, thus impairing Treg cell expansion (9). In this context, and metabolic signaling that are dependent on sterol regulatory-

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another key sensor and regulator of cellular energy metabolism is element binding proteins (SREBPs) in Treg cells altered their
represented by AMP-activated protein kinase (AMPK), which functional fitness, promoting antitumor immune responses (20).
regulates T cell metabolism, differentiation, and effector functions Accordingly, genetic or pharmacological inhibition of fatty acid
by inhibiting mTOR kinase activity. According to what has been binding protein 5 (FABP5) or CD36, a known fatty acid translo-
previously mentioned, compelling evidence has reported that the case importing fatty acids, leads to altered lipid metabolism, with
addition of metformin, an AMPK activator, to naive T cell cul- consequent impaired Treg cell suppressive activity (21, 22). In
ture dose-dependently inhibited differentiation of Th1 and Th17 addition, the mevalonate pathway has also been shown to promote
cells while promoting the development of Treg cells (10). the upregulation of Treg cellassociated suppressive molecules
Oxidative metabolism. An open question arising from the liter- (i.e., CTLA-4 and ICOS), and inhibition of this pathway impairs
ature is the type of metabolism specifically required by Treg cells Treg cell function (23, 24). Recently, it has been shown that fatty
to acquire their suppressive activity. Some reports support the acids can also impact thymocyte programming, conditioning
idea that glycolysis activation may selectively compromise Treg their subsequent differentiation into peripheral Treg cells. Specifi-
cell function and stability in vivo; indeed, mice overexpress- cally, Lin et al. (25) reported that low levels of oleic acid in thy-
ing Glut1 develop spontaneous autoimmunity, with Treg cells mic cells promote persistent epigenetic changes in naive CD41
being more glycolytic and expanded in number, but less suppres-
T cells that can drive their differentiation into Treg cells upon
sive (11). In line with this evidence, oxidative metabolism seems
TCR-mediated activation. The microenvironmental cues driv-
to be required for Treg cell suppressive function, as these cells
ing Treg cell generation and function also include some short-
display greater mitochondrial mass and reactive oxygen species
chain fatty acids (SCFAs), produced by commensal bacteria
(ROS) production than do Tconv cells, with ROS levels correlat-
during starch fermentation, which are able to promote extrathymic
ing with Foxp3 expression (12). Moreover, deletion of regulators
generation of Treg cells (26). Among these microbial metabolites,
of mitochondrial activity, such as peroxisome proliferator-
butyrate and propionate, for example, can act at the molecular
activated receptor g coactivator 1a (Pgc1a) or sirtuin 3 (Sirt3),
level in naive CD41 T cells sustaining Foxp3 induction and Treg
is associated with inhibition of Treg cell activity both in vitro
and in vivo (12). In this context, further studies have also iden- cell differentiation (27). In addition to the above-described
tified complex III of the electron transport chain (13) and the pathways, amino acid catabolism has also been implicated in the
mitochondrial transcription factor A (Tfam) (14) as important modulation of Treg cell regulatory mechanisms. Specifically, the
elements required for Treg cell suppressive function, as their expression of IDO, an enzyme involved in tryptophan metabo-
inhibition impaired Foxp3 expression with consequent reduced lism, and the production of several metabolites from the kynure-
Treg cell maintenance. nine pathway have been reported to positively regulate Treg cell
Glucose metabolism. Although initial studies have indicated that development and function. IDO-mediated local tryptophan
murine Treg cells predominantly engage oxidative metabolism (2) depletion leads to inhibition of the Akt-mTOR pathway and
to sustain their own function, metabolic adaptations of these cells upregulation of FoxO3a, with consequent acquisition of a Treg
are context-dependent, and recent findings have reported that cell highly suppressive phenotype (28).
murine Ki671 splenic Treg cells express high levels of the glucose In conclusion, further studies are certainly needed to solve these
transporter Glut1 (11), thus suggesting that they also need glu- conflicting results on the specific metabolic pathway engaged by
cose metabolism for their function. Similarly, human Treg cells Treg cells. This apparent discrepancy in their metabolic asset
display a high glycolytic rate ex vivo, in agreement with their high may be ascribed to the considerable heterogeneity and intrinsic
proliferative state (8, 11, 15) in vivo. When induced to proliferate variety of Treg cells, which can differ for their origin (thymic
in vitro, Treg cells engage both glycolysis and FAO, in contrast to versus peripheral versus in vitro induced), phenotypic characteris-
Tconv cells, which predominantly use an oxidative metabolism ex tics, lineage stability and function, as well as tissue-specific localiza-
vivo but mainly rely on glycolysis for their in vitro expansion tion and cytokine production. Moreover, the vast majority of the
(2, 16). In line with this evidence, the generation of human induc- experimental results obtained on Treg cell metabolism derive from
ible Treg (iTreg) cells in vitro, through suboptimal TCR-mediated studies on murine cells, whose functional and phenotypic features
stimulation, is tightly dependent on glycolysis, as the glyco- are not always overlapping with those of human Treg cells, thus
lytic enzyme enolase-1 has been shown to control the expression explaining the differential engagement of specific metabolic path-
of FOXP3 splicing variant containing exon2 (FOXP3-E2), nec- ways between the two species. However, it seems quite evident that
essary for Treg cell suppressive function (17). In tumor settings, Treg cell can plastically manipulate their intracellular metabolic
Pacella et al. (18) have reported that both human and murine pathways to meet energy demand and to adapt their function
tumor-associated Treg cells display an advantage in glucose to environmental changes.
The Journal of Immunology 1861

Metabolic control of Treg cell homeostasis in autoimmune diseases Th1-like Treg cells) (32), resulting in impaired suppressive
Multiple sclerosis. Compelling evidence has indicated that Treg activity as a consequence of PI3K-AKT-FOXO1/3 pathway
cell disfunction plays a key role in the pathogenesis of autoim- activation (33).
mune disorders of the CNS. Similarly to all different immune cell Regarding Treg cellspecific intracellular metabolic pathways,
subsets, Treg cell differentiation and function are finely regulated as we described above, glycolysis has been shown to promote the
by the activation of specific metabolic programs, whose alterations induction and generation of iTreg cells from Tconv cells in vitro,
may be associated with Treg cell dysfunctional activity, resulting as glycolysis controls the expression of FOXP3-E2 through
in the onset of autoimmune diseases, such as multiple sclerosis the glycolytic enzyme enolase-1. Interestingly, Tconv cells
(MS). Specifically, Treg cells from people with relapsing-remitting from RRMS displayed a reduced glycolysis engagement that
MS (RRMS) are characterized by hyperactivation of the meta- was associated with impaired Treg cell generation and suppres-
bolic sensor mTOR kinase, which associates with decreased sive activity and decreased induction of FOXP3-E2 (17) (Fig. 1).
FOXP3 expression and impaired Treg cell proliferative poten-

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Pompura et al. (34) have recently suggested that although
tial (29) (Fig. 1). As we previously mentioned, the mTOR glycolytic metabolism can support Treg cell induction and
pathway is also activated by the adipocytokine leptin, and, proliferation, their suppressive activity is mainly sustained by
interestingly, leptin production was significantly increased in FAO-driven oxidative phosphorylation (OXPHOS). Specifi-
both the serum and cerebrospinal fluid of RRMS patients, and cally, Treg cells are able to sense oleic acid, the most abun-
an inverse correlation between serum leptin levels and Treg cell dant long-chain free fatty acid in adipose tissue of healthy
percentage was also observed in these subjects. The correlation individuals. Oleic acid stimulates FAO-driven OXPHOS metab-
between leptin and Treg cell frequency is further supported by
olism, which induces FOXP3 expression and STAT5 phos-
the observations showing that leptin-deficient (ob/ob) and leptin
phorylation, thereby enhancing Treg cell suppressive activity.
receptordeficient (db/db) mice are less prone to develop auto-
Interestingly, the oleic acid concentration in the adipose tissue
immunity and are characterized by a significant increase in
Treg cell number (30). Interestingly, in RRMS, Treg cells from MS subjects was significantly lower than that observed in
showed impaired proliferation and reduced IL-2 secretion after healthy individuals, and the exposure of MS Treg cells to oleic
incubation with a leptin-neutralizing mAb (29). Consistent acid partially recovered their impaired function. Furthermore,
with these observations, rapamycin-induced mTOR inhibition while the transcriptome of MS Treg cells closely resembles that
suppressed experimental autoimmune encephalomyelitis (EAE), of Treg cells exposed to a proinflammatory agent (such as arachi-
the mouse model of MS, and promoted selective Treg cell donic acid), treatment with oleic acid changes the expression pat-
expansion (31). During inflammation, several functional changes tern of MS Treg cells toward a profile resembling that observed
have been described in Treg cells, which, for example, can acquire in healthy subjects. These data suggest that the tissue microenvi-
effector properties in MS subjects and express IFN-g (termed ronment may influence Treg cell metabolism, impacting their

FIGURE 1. Schematic representation of the main altered metabolic pathways in Treg cells from multiple sclerosis (MS) subjects. Treg cell from MS subjects (right)
is characterized by different metabolic alterations as compared with a Treg cell from healthy subjects (left), such as 1) hyperactivation of the mTOR pathway associated
with decreased FOXP3 expression and impaired Treg cell proliferative potential; (2) reduced glycolysis in Tconv cells associated with altered generation of induced Treg
(iTreg) cells and decreased induction of the FOXP3-E2; 3) impaired induction of the NRF-2/SLC7A11 axis upon signals of pseudo-starvation, leading to reduced Treg
cell proliferation and impaired reduced glutathione (GSH) production and ROS scavenging; and 4) lower levels of oleic acid in the adipose tissue, associated with
impaired stimulation of FAO-driven OXPHOS metabolism and altered Foxp3 expression.
1862 BRIEF REVIEWS: TREG CELL METABOLISM IN AUTOIMMUNITY

function, and that an altered lipid profile in MS may contribute to carboxylase 1 (ACC1), a crucial enzyme involved in de novo syn-
Treg cell dysfunctional activity (34). thesis of fatty acids, led to suppression of the glycolytic-lipogenic
In addition to the above-described pathways, alteration of pathway and hampered Th17 cell generation, also enhancing Treg
IDO, involved in amino acid catabolism, has also been implicated cell development. In addition, T cellspecific ACC1-deficient
in alteration of Treg cells during MS. Specifically, IDO-deficient mice (TACC-1) were protected from EAE development, show-
mice are characterized by exacerbated EAE, associated with ing a lower frequency of IL-17 and IFN-gproducing CD41
impairment of Treg cell function. Conversely, in vitro treatment T cells with a concomitant increase in Treg cell percentage within
of naive splenocytes with 3-hydroxyanthranilic acid (3-HAA), a the CNS (41). In summary, all of this evidence suggests the exis-
downstream tryptophan metabolite, promoted Treg cell induc- tence of complex pathophysiological mechanisms related to Treg
tion, and its administration in vivo reduced the EAE severity by cell metabolic alterations during MS, whose modulation can rep-
suppressing Th17 responses and skewing the immune response resent a promising therapeutic approach for disease treatment.
toward a regulatory phenotype (35). Consistent with these find- Systemic lupus erythematosus. Systemic lupus erythematosus

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ings, PBMCs from MS patients are characterized by reduced (SLE) is an autoimmune disease characterized by chronic inflam-
expression and activity of the enzyme IDO1, which is associated mation and an abnormal response with autoantibody production
with decreased amino acid catabolism and impaired Treg cell against self-antigens (42), leading to heterogeneous clinical mani-
frequency (36). Recent evidence has highlighted the key role festations, including arthritis, skin disease, blood cell abnormali-
exerted by amino acid transporters (solute carriers) in the control ties, and kidney damage (43). Several studies have reported the
of Treg cell homeostasis under normal and pathological condi- presence of quantitative, functional, and metabolic abnormalities
tions. In this context, it has been recently shown that Treg cell specifically in Treg cell compartment as one of the main SLE
proliferation induced by signal of pseudo-starvation (achieved by pathogenetic mechanisms (4448). Specifically, Treg cells from
either mTOR inhibition or leptin neutralization) was dependent SLE patients are characterized by giant mitochondria that are
on the induction of the cystine/glutamate antiporter solute carrier more prone to hyperpolarization, increased active oxidation prod-
family 7 member 11 (SLC7A11), whose expression was controlled ucts, and enhanced ATP consumption (49). This condition is also
by the NF erythroid 2related factor 2 (NRF-2), a key molecular associated with an increased mitochondrial biosynthesis in Treg
determinant involved in protection against oxidative stress. Induc- cells from SLE patients, which promotes excessive generation of
tion of the NRF-2/SLC7A11 axis in Treg cells was impaired in oxidation products; these agents can alter protein/lipid complexes
subjects with RRMS, concomitantly with reduced Treg cell pro- of the respiratory chain and impair mitochondrial function, fur-
liferative capacity and impaired ROS scavenging (37) (Fig. 1); ther increasing intracellular oxidation, DNA damage, and Treg
interestingly, in vivo treatment of RRMS subjects with dimethyl cell death, which ultimately lead to altered self-tolerance (49, 50)
fumarate (DMF) restored SLC7A11 induction, also recovering (Fig. 2).
Treg cell expansion.
A recent report has also highlighted the key role of mitochon-
drial metabolism in the control of Treg cell fate in MS. Indeed,
Alissafi et al. (38) have shown that increased mitochondrial oxida-
tive stress and severe DNA damage are associated with Treg cell
death in patients with MS. In addition, scavenging of mitochon-
drial ROS (achieved either chemically or by inducing the expres-
sion of the antioxidant enzyme catalase) in Treg cells from EAE
mice prevented DNA damage and Treg cell death, while reducing
Th1 and Th17 activation.
As we reported above, SCFAs, bacterial fermentation prod-
ucts derived from the gut microbiota, have been shown to play
an important role in regulating the recruitment, activation, and
differentiation of Treg cells. In the animal model of MS, disease
exacerbation and expansion of Th1 and/or Th17 cell subsets in
the small intestine have been associated with a reduction in SCFA
levels (Fig. 1). Treatment of EAE mice with SCFAs resulted in an
improvement in the disease course and an increased frequency of
gut-associated Treg cells (39). These data have also been con-
firmed in human samples, as Duscha et al. (40) have shown
reduced levels of the SCFA propionic acid in the sera and stool
samples of MS subjects and an altered microbiome character- FIGURE 2. Schematic representation of the main Treg cell metabolic alter-
ized by the depletion of specific SCFA-producing bacteria, such ations in systemic lupus erythematosus. (1) Treg cells from systemic lupus ery-
as Butyricimonas. Interestingly, propionic acid supplementation thematosus (SLE) subjects are characterized by giant mitochondria, increased
in MS patients significantly increased Treg cell frequency and generation of oxidation products, and enhanced ATP consumption associated
their suppressive capacity, leading to an improved disease pro- with DNA damage and Treg cell death; (2) inhibition of calcium/calmodulin-
dependent protein kinase 4 (CaMK4) enhances Treg cell immunosuppressive
gression, a significant reduction in annual relapse rate, and an
function through modulation of intracellular metabolism; and (3) conditional
increased subcortical gray matter volume (40). deletion of the SLE susceptibility gene Esrrg in Treg cells results in increased
It has also been shown that perturbation of the endogenous ROS generation, impaired oxygen consumption and ATP and NAD1 pro-
fatty acid synthesis pathway has a remarkable impact on Treg duction, reduced expression of IL2ra and Trbc1, and impaired TGF-b signal-
and Th17 cell development. Indeed, inhibition of acetyl-CoA ing and increased mTOR activation.
The Journal of Immunology 1863

It has also been reported that CD41 T cells from SLE patients this context, Duan et al. (10) observed that treatment of female
and lupus-prone mice are characterized by increased mTORC1 NOD mice with the AMPK activator metformin significantly
activation, similarly to what has been observed in other autoim- reduced autoimmune insulitis, decreased the number of proin-
mune diseases. The altered regulation of mTORC1 leads to ele- flammatory CD41 T cells, and enhanced Treg cell percentage in
vated IL-17, IL-4 producing double-negative T cell expansion, the spleen (Table I). As we have previously mentioned, the kinase
and depletion of the Treg cell compartment (51, 52). mTOR, a target of AMPK, plays a critical role in the control of
Recently, Scherlinger et al. (53) have reported that Treg cell Treg cell metabolism. Similarly to what has been described for
defective function in SLE could be restored by modulating their MS, modulation of mTOR activity can affect Treg cell expansion
glycolytic metabolism. Specifically, they found that in lupus- and function also during diabetes, as in vivo administration of
prone mice a T cellspecific deletion of calcium/calmodulin- rapamycin has been shown to protect NOD mice from T1D pro-
dependent protein kinase 4 (CaMK4), which physiologically gression and restore long-term tolerance to self-antigens through
promotes aerobic glycolysis and suppresses oxidative metabo- expansion of the Treg cell compartment (55) (Table I). In line

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lism, resulted in Treg cell expansion and disease improvement. with these observations, He et al. (56) tested as a possible treat-
Corroborating this evidence, pharmacological inhibition of ment for T1D the combination of rapamycin and g-aminobutyric
CaMK4 in Treg cells from SLE subjects enhanced Treg cell acid (GABA), an amino acid acting as an inhibitory neurotrans-
immunosuppressive function (Fig. 2). mitter within the CNS. The authors found that this treatment
In addition to glycolysis, it has been observed that some SLE significantly improved T1D progression in NOD mice; in
susceptibility genes, including the estrogen-related receptor g particular, rapamycin increased the proportion of Treg cells, while
(Esrrg), are also able to modulate mitochondrial metabolism and GABA sustained islet function, leading to a decrease in blood glu-
consequently control Treg cell function (54). In this context, cose levels and a significant improvement in insulin and C-peptide
conditional deletion of the Esrrg in Treg cells (Esrrg-cKO [condi- concentrations, bringing them to levels comparable to those of
tional knockout]) resulted in defective mitochondrial function nondiabetic mice (56).
with increased ROS production, impaired oxygen consumption, The relevance of in vivo treatment with rapamycin has been
as well as diminished ATP and NAD1 production. In parallel, corroborated also in human settings in patients with T1D. It has
CD41 T cells from Esrrg-cKO mice produced more IFN-g, been shown that rapamycin did not modify Treg cell number,
and Esrrg-cKO Treg cells showed reduced expression of genes phenotype, and their ability to proliferate and produce anti-
implicated in Treg cell suppressive function, such as IL2ra inflammatory cytokines, but rather it was able to increase their
and Trbc1, impaired TGF-b signaling, and increased mTOR suppressive capacity (57). In parallel, results from other studies
activation. Overall, these results indicate that Esrrg deficiency in demonstrated that treatment of NOD mice with a combination
Treg cells causes a widespread activation of CD41 T cells and of rapamycin and IL-2 effectively reduced autoimmune diabe-
autoantibody production, promoting SLE (54). Supporting the tes, even though the efficacy of this treatment has not been fully
mouse data, the authors also found that SLE patients displayed confirmed on humans in a phase 1 clinical trial. Indeed, it has
reduced Esrrg expression in CD41 T cells as compared with been observed that although rapamycin/IL-2 combination ther-
healthy controls (54) (Fig. 2). apy led to an increase in Treg cells during the first month of
Taken together, these findings suggest that, because mitochon- therapy, clinical and metabolic data showed a transient worsen-
drial dysfunction may contribute to the pathogenesis of SLE, tar- ing in all of the enrolled subjects (58) (Table I).
geting oxidative metabolism may represent a novel approach for In addition to the above-mentioned drugs/molecules, some
the treatment of systemic autoimmune diseases. metabolites of the glycolytic pathway also can modulate Treg
Type 1 diabetes. Type 1 diabetes (T1D) is a chronic autoim- cell generation and function, influencing T1D incidence. Indeed,
mune disease characterized by a progressive T cellmediated treatment of multiple low doses of streptozotocin (MLDS)-
destruction of insulin-producing pancreatic b cells, leading to induced T1D mice with ethyl pyruvate, a stable pyruvate derivate,
loss of insulin production and high blood glucose levels. Changes reduced T1D incidence predominantly by enhancing Treg cell
in cellular metabolism have been reported to influence both the differentiation, proliferation, recruitment into the pancreas, and
severity of autoimmune insulitis and the development of T1D. In their suppressive activity (59) (Table I). In addition, D-mannose,

Table I. Effect of metabolic modulators on different T cell subsets from type 1 diabetes (T1D)

Compound Cell Subset Effect Species Reference

Metformin CD41 T/Treg cells Reduction of CD41 T cell Mouse Duan et al., 2019 (10)
number and increase of Treg cell
percentage
Rapamycin Treg cells Treg cell expansion and induction Mouse Battaglia et al., 2006 (55)
of their suppressive capacity
Rapamycin 1 IL-2 Treg cells Increase of Treg cell number Human Long et al., 2012 (58)
Ethyl pyruvate Treg cells Promotion of Treg cell Mouse Koprivica et al., 2018 (59)
differentiation and proliferation
D-mannose CD41 T/Treg cells Reduction of glycolysis and Mouse Zhang et al., 2017 (60)
induction of FAO in CD41 T
cells; expansion of Treg cell
compartment
Alpha-lipoic acid Th1/Treg cells Reduction of Th1 cells and Mouse Huang et al., 2022 (61)
increase in Treg cell frequency
Butyrate Treg cells Increase of Treg cell number Mouse Jacob et al., 2020 (62)
1864 BRIEF REVIEWS: TREG CELL METABOLISM IN AUTOIMMUNITY

a C-2 epimer of glucose, also has been shown to display immu- during disease progression. Indeed, in a randomized, double-
noregulatory properties, as levels of D-mannose decreased gly- blind, placebo-controlled trial, treatment of SLE patients with
colysis engagement while promoting supraphysiological FAO N-acetylcysteine, a GSH precursor, increased GSH levels in
in T cells and expanded the Treg cell compartment, thus sup- PBLs and inhibited the mTOR pathway, expanding Treg cells
pressing immunopathology in mouse models of autoimmune and thus leading to improvement of disease activity (68). In
diabetes and airway inflammation (60) (Table I). addition, mTOR inhibition achieved by rapamycin treatment in
As concerns mitochondrial metabolism, a critical regulator of SLE patients was also found to reduce autoantibody production
this metabolic pathway is represented by the alpha-lipoic acid and improve proteinuria, resulting in alleviation of disease activ-
(ALA), a fatty acid that acts as the cofactor of pyruvate dehydro- ity (69) associated with expansion of Treg cells in vivo (70).
genase complex, which catalyzes the oxidative decarboxylation Taken together, these data support the idea that the induction
of a-keto acids. ALA is reported to exert immunomodulatory of a specific cellular metabolism, able to favor the generation and
effects on Treg cells with possible therapeutic potential for T1D function of Treg cells, may represent a promising therapeutic

Downloaded from http://journals.aai.org/jimmunol/article-pdf/212/12/1859/1657757/ji2400079.pdf by Chulalongkorn Univ Lib/Fac of Med user on 08 June 2024
management. Indeed, ALA treatment in NOD mice has been strategy for several autoimmune diseases.
associated with a reduction of Th1 and increase of Treg cell fre-
quency, mitigating diabetes incidence and promoting survival of
syngeneic and allogeneic islet grafts after their transplantation Conclusions
(Table I). Furthermore, in vitro ALA treatment enhanced the Compelling experimental evidence has shown that specific intra-
differentiation of CD41 T cells into iTreg cells, whose adoptive cellular metabolic programs in Treg cells are able to regulate
transfer into NOD mice led to an improved outcome of pan- Treg cell generation and are closely linked to their phenotype
creatic islet grafts (61). and acquisition of suppressive function, thus defining their cell
As described for MS, SCFAs can regulate Treg cell homeo- identity. Despite the considerable progress made by research in
stasis, thereby influencing T1D course. In this context, Jacob this area, the precise understanding of how modulation of meta-
et al. (62) reported that administration of butyrate to female bolic pathways may impact Treg cell fate has been hampered by
NOD mice after the onset of hyperglycemia (1525 wk of age) the heterogeneity of Treg cells, which may display phenotypic
or at 4 wk of age (early intervention group) led to an increase and functional features that are not always overlapping. The view
in Treg cells in the colon, mesenteric lymph nodes, and Peyer’s that Treg cells use only oxidative metabolism has been replaced by
patches (Table I). These events clinically translated into a signifi- the notion that they can employ both glycolysis and OXPHOS,
cant reduction of hyperglycemia in diabetic mice and a delay in often using also other metabolic pathways, whose activation is con-
diabetes onset in the early intervention group. text-dependent and can be plastically modulated according to the
In summary, all of these data suggest that several metabolic cell’s energy requirements.
compounds/intermediates can modulate immune system func- In several autoimmune diseases, Treg cells are characterized by
tion, acting on its regulatory arm and enhancing its immunosup- an altered cell metabolism, resulting in their impaired generation
pressive properties in mouse models of T1D and in clinical trials, and function; therefore, a rapidly growing research effort is trying
although further studies are needed to understand whether and to outline the most effective way to drive Treg cell metabolism
how these treatments specifically act on Treg cell metabolism. to convey their functional activity.
Although there are still few therapeutic strategies aimed at tar-
Therapeutic targeting of metabolism in autoimmunity geting the intracellular metabolism of Treg cells in the clinical
setting, these represent a promising approach in the context of
Experimental data from the literature suggest that Treg cell meta-
several pathological conditions, including cancer, transplantation
bolic dysfunction can contribute to the pathogenesis of several
and autoimmunity.
autoimmune diseases (63). Given the high sensitivity of Treg cells
to metabolic cues, enhancing their immunosuppressive activity by
modulating cellular metabolism may represent a potential novel
and promising therapeutic strategy for the management of auto-
Acknowledgments
Parts of the figures were drawn by using pictures from Servier Medical Art
immunity. In this context, metformin, a worldwide milestone (https://smart.servier.com).
drug in the treatment of patients with type 2 diabetes (64), has
also proven effective in improving the course of other autoim-
mune diseases, such as inflammatory bowel disease and EAE, by Disclosures
promoting Treg cell generation and inhibiting Th17 cell differen- The authors have no financial conflicts of interest.
tiation (65, 66).
Another metabolic modulator and candidate for the treatment
of autoimmune diseases is itaconate, a metabolite derived from References
1. Pålsson-McDermott, E. M., and L. A. J. O’Neill. 2020. Targeting immunometab-
the mitochondrial tricarboxylic acid cycle, which is able to sup- olism as an anti-inflammatory strategy. Cell Res. 30: 300314.
press glycolysis and oxidative phosphorylation in T cells, inhibit- 2. Michalek, R. D., V. A. Gerriets, S. R. Jacobs, A. N. Macintyre, N. J. MacIver, E. F.
ing Th17 and promoting Treg cell differentiation. Corroborating Mason, S. A. Sullivan, A. G. Nichols, and J. C. Rathmell. 2011. Cutting edge: dis-
tinct glycolytic and lipid oxidative metabolic programs are essential for effector and
this evidence, the adoptive transfer of itaconate-treated Th17- regulatory CD41 T cell subsets. J. Immunol. 186: 32993303.
polarizing T cells has been associated with amelioration of EAE 3. Pearce, E. L., M. C. Walsh, P. J. Cejas, G. M. Harms, H. Shen, L. S. Wang, R. G.
Jones, and Y. Choi. 2009. Enhancing CD8 T-cell memory by modulating fatty
course and progression (67). acid metabolism. Nature 460: 103107.
Oxidative stress has been widely implicated in the pathogenesis 4. Woods, S. C., R. J. Seeley, and D. Cota. 2008. Regulation of food intake through
hypothalamic signaling networks involving mTOR. Annu. Rev. Nutr. 28: 295311.
of SLE, and the amount of cysteine, a precursor of the antioxi- 5. Blouet, C., H. Ono, and G. J. Schwartz. 2008. Mediobasal hypothalamic p70 S6
dant agent reduced glutathione (GSH), decreases significantly kinase 1 modulates the control of energy homeostasis. Cell Metab. 8: 459467.
The Journal of Immunology 1865

6. Battaglia, M., A. Stabilini, and M. G. Roncarolo. 2005. Rapamycin selectively expands 32. Dominguez-Villar, M., C. M. Baecher-Allan, and D. A. Hafler. 2011. Identification
CD41CD251FoxP31 regulatory T cells. Blood 105: 47434748. of T helper type 1-like, Foxp31 regulatory T cells in human autoimmune disease.
7. Strauss, L., M. Czystowska, M. Szajnik, M. Mandapathil, and T. L. Whiteside. Nat. Med. 17: 673675.
2009. Differential responses of human regulatory T cells (Treg) and effector T cells 33. Kitz, A., M. de Marcken, A. S. Gautron, M. Mitrovic, D. A. Hafler, and M. Dominguez-
to rapamycin. PLoS One 4: e5994. Villar. 2016. AKT isoforms modulate Th1-like Treg generation and function in human
8. Procaccini, C., V. De Rosa, M. Galgani, L. Abanni, G. Calı̀, A. Porcellini, F. Carbone, autoimmune disease. EMBO Rep. 17: 11691183.
S. Fontana, T. L. Horvath, A. La Cava, and G. Matarese. 2010. An oscillatory switch 34. Pompura, S. L., A. Wagner, A. Kitz, J. LaPerche, N. Yosef, M. Dominguez-Villar,
in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33: 929941. and D. A. Hafler. 2021. Oleic acid restores suppressive defects in tissue-resident
9. De Rosa, V., A. La Cava, and G. Matarese. 2017. Metabolic pressure and the FOXP3 Tregs from patients with multiple sclerosis. J. Clin. Invest. 131: e138519.
breach of immunological self-tolerance. Nat. Immunol. 18: 11901196. 35. Yan, Y., G. X. Zhang, B. Gran, F. Fallarino, S. Yu, H. Li, M. L. Cullimore, A. Rostami,
10. Duan, W., Y. Ding, X. Yu, D. Ma, B. Yang, Y. Li, L. Huang, Z. Chen, J. Zheng, and H. Xu. 2010. IDO upregulates regulatory T cells via tryptophan catabolite and sup-
and C. Yang. 2019. Metformin mitigates autoimmune insulitis by inhibiting Th1 presses encephalitogenic T cell responses in experimental autoimmune encephalomyeli-
and Th17 responses while promoting Treg production. Am. J. Transl. Res. 11: tis. J. Immunol. 185: 59535961.
23932402. 36. Negrotto, L., and J. Correale. 2017. Amino acid catabolism in multiple sclerosis
11. Gerriets, V. A., R. J. Kishton, M. O. Johnson, S. Cohen, P. J. Siska, A. G. Nichols, affects immune homeostasis. J. Immunol. 198: 19001909.
M. O. Warmoes, A. A. de Cubas, N. J. MacIver, J. W. Locasale, et al. 2016. Foxp3 37. Procaccini, C., S. Garavelli, F. Carbone, D. Di Silvestre, C. La Rocca, D. Greco,
and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppres- A. Colamatteo, M. T. Lepore, C. Russo, G. De Rosa, et al. 2021. Signals of

Downloaded from http://journals.aai.org/jimmunol/article-pdf/212/12/1859/1657757/ji2400079.pdf by Chulalongkorn Univ Lib/Fac of Med user on 08 June 2024
sion. Nat. Immunol. 17: 14591466. pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant
12. Beier, U. H., A. Angelin, T. Akimova, L. Wang, Y. Liu, H. Xiao, M. A. Koike, in the control of Treg cell proliferative potential. Immunity 54: 15431560.e6.
S. A. Hancock, T. R. Bhatti, R. Han, et al. 2015. Essential role of mitochondrial 38. Alissafi, T., L. Kalafati, M. Lazari, A. Filia, I. Kloukina, M. Manifava, J. H. Lim,
energy metabolism in Foxp31 T-regulatory cell function and allograft survival. V. I. Alexaki, N. T. Ktistakis, T. Doskas, et al. 2020. Mitochondrial Oxidative
FASEB J. 29: 23152326. Damage Underlies Regulatory T Cell Defects in Autoimmunity. Cell Metab. 32:
13. Weinberg, S. E., B. D. Singer, E. M. Steinert, C. A. Martinez, M. M. Mehta, 591604.e7.
I. Martı́nez-Reyes, P. Gao, K. A. Helmin, H. Abdala-Valencia, L. A. Sena, et al. 39. Haghikia, A., S. Jörg, A. Duscha, J. Berg, A. Manzel, A. Waschbisch, A. Hammer,
2019. Mitochondrial complex III is essential for suppressive function of regulatory D. H. Lee, C. May, N. Wilck, et al. 2015. Dietary fatty acids directly impact central
T cells. Nature 565: 495499. nervous system autoimmunity via the small intestine. Immunity 43: 817829.
14. Fu, Z., J. Ye, J. W. Dean, J. W. Bostick, S. E. Weinberg, L. Xiong, K. N. Oliff, 40. Duscha, A., B. Gisevius, S. Hirschberg, N. Yissachar, G. I. Stangl, E. Dawin,
Z. E. Chen, D. Avram, N. S. Chandel, and L. Zhou. 2019. Requirement of mito- V. Bader, S. Haase, J. Kaisler, C. David, et al. 2020. Propionic Acid Shapes the
chondrial transcription factor A in tissue-resident regulatory T cell maintenance Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism. Cell 180:
and function. Cell Rep. 28: 159171.e4. 10671080.e16.
15. Vukmanovic-Stejic, M., E. Agius, N. Booth, P. J. Dunne, K. E. Lacy, J. R. Reed, 41. Berod, L., C. Friedrich, A. Nandan, J. Freitag, S. Hagemann, K. Harmrolfs,
T. O. Sobande, S. Kissane, M. Salmon, M. H. Rustin, and A. N. Akbar. 2008. The A. Sandouk, C. Hesse, C. N. Castro, H. Bähre, et al. 2014. De novo fatty acid syn-
kinetics of CD41Foxp31 T cell accumulation during a human cutaneous antigen- thesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20:
specific memory response in vivo. J. Clin. Invest. 118: 36393650. 13271333.
16. Buck, M. D., D. O’Sullivan, and E. L. Pearce. 2015. T cell metabolism drives 42. Arbuckle, M. R., M. T. McClain, M. V. Rubertone, R. H. Scofield, G. J. Dennis,
immunity. J. Exp. Med. 212: 13451360. J. A. James, and J. B. Harley. 2003. Development of autoantibodies before the clin-
17. De Rosa, V., M. Galgani, A. Porcellini, A. Colamatteo, M. Santopaolo, C. Zuchegna, ical onset of systemic lupus erythematosus. N. Engl. J. Med. 349: 15261533.
A. Romano, S. De Simone, C. Procaccini, C. La Rocca, et al. 2015. Glycolysis con- 43. Moulton, V. R., A. Suarez-Fueyo, E. Meidan, H. Li, M. Mizui, and G. C. Tsokos.
2017. Pathogenesis of human systemic lupus erythematosus: a cellular perspective.
trols the induction of human regulatory T cells by modulating the expression of
Trends Mol. Med. 23: 615635.
FOXP3 exon 2 splicing variants. Nat. Immunol. 16: 11741184.
44. Álvarez-Rodrı́guez, L., V. Martı́nez-Taboada, J. Calvo-Alén, I. Beares, I. Villa, and
18. Pacella, I., C. Procaccini, C. Focaccetti, S. Miacci, E. Timperi, D. Faicchia,
M. López-Hoyos. 2019. Altered Th17/Treg ratio in peripheral blood of systemic
M. Severa, F. Rizzo, E. M. Coccia, F. Bonacina, et al. 2018. Fatty acid metabolism
lupus erythematosus but not primary antiphospholipid syndrome. Front. Immunol.
complements glycolysis in the selective regulatory T cell expansion during tumor
10: 391.
growth. Proc. Natl. Acad. Sci. USA 115: E6546E6555.
45. Talaat, R. M., S. F. Mohamed, I. H. Bassyouni, and A. A. Raouf. 2015. Th1/Th2/
19. Kishore, M., K. C. P. Cheung, H. Fu, F. Bonacina, G. Wang, D. Coe, E. J. Ward,
Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients:
A. Colamatteo, M. Jangani, A. Baragetti, et al. 2017. Regulatory T cell migration is
Correlation with disease activity. Cytokine 72: 146153.
dependent on glucokinase-mediated glycolysis. Immunity 47: 875889.e10.
46. Chen, M., X. Chen, and Q. Wan. 2018. Altered frequency of Th17 and Treg cells in
20. Lim, S. A., J. Wei, T. M. Nguyen, H. Shi, W. Su, G. Palacios, Y. Dhungana,
new-onset systemic lupus erythematosus patients. Eur. J. Clin. Invest. 48: e13012.
N. M. Chapman, L. Long, J. Saravia, et al. 2021. Lipid signalling enforces func-
47. Zhu, Y., Y. Huang, B. Ming, X. Wu, Y. Chen, and L. Dong. 2019. Regulatory T-cell
tional specialization of Treg cells in tumours. Nature 591: 306311. levels in systemic lupus erythematosus patients: a meta-analysis. Lupus 28: 445454.
21. Wang, H., F. Franco, Y. C. Tsui, X. Xie, M. P. Trefny, R. Zappasodi, S. R. Mohmood, 48. La Cava, A. 2018. Tregs in SLE: an update. Curr. Rheumatol. Rep. 20: 6.
J. Fernández-Garcı́a, C. H. Tsai, I. Schulze, et al. 2020. CD36-mediated metabolic 49. Zhao, X., S. Wang, S. Wang, J. Xie, and D. Cui. 2022. mTOR signaling: a pivotal
adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. player in Treg cell dysfunction in systemic lupus erythematosus. Clin. Immunol. 245:
21: 298308. 109153.
22. Field, C. S., F. Baixauli, R. L. Kyle, D. J. Puleston, A. M. Cameron, D. E. Sanin, 50. Ohl, K., and K. Tenbrock. 2021. Oxidative stress in SLE T cells, is NRF2 really
K. L. Hippen, M. Loschi, G. Thangavelu, M. Corrado, et al. 2020. Mitochondrial the target to treat? Front. Immunol. 12: 633845.
integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg sup- 51. Vukelic, M., M. Kono, and G. C. Tsokos. 2020. T cell metabolism in lupus.
pressive function. Cell Metab. 31: 422437.e5. Immunometabolism 2: e200009.
23. Zeng, H., K. Yang, C. Cloer, G. Neale, P. Vogel, and H. Chi. 2013. mTORC1 52. Yin, Y., S. C. Choi, Z. Xu, D. J. Perry, H. Seay, B. P. Croker, E. S. Sobel, T. M. Brusko,
couples immune signals and metabolic programming to establish Treg-cell function. and L. Morel. 2015. Normalization of CD41 T cell metabolism reverses lupus. Sci.
Nature 499: 485490. Transl. Med. 7: 274ra18.
24. Thurnher, M., and G. Gruenbacher. 2015. T lymphocyte regulation by mevalonate 53. Scherlinger, M., W. Pan, R. Hisada, A. Boulougoura, N. Yoshida, M. Vukelic,
metabolism. Sci. Signal. 8: re4. M. Umeda, S. Krishfield, M. G. Tsokos, and G. C. Tsokos. 2022. Phosphofructo-
25. Lin, L., M. Hu, Q. Li, L. Du, L. Lin, Y. Xue, F. Zheng, F. Wang, K. Liu, Y. Wang, kinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic
et al. 2024. Oleic acid availability impacts thymocyte preprogramming and subsequent autoimmunity. Sci. Adv. 8: eadc9657.
peripheral Treg cell differentiation. Nat. Immunol. 25: 5465. 54. Li, W., M. Gong, Y. P. Park, A. S. Elshikha, S. C. Choi, J. Brown, N. Kanda,
26. Smith, P. M., M. R. Howitt, N. Panikov, M. Michaud, C. A. Gallini, Y. M. Bohlooly, W. I. Yeh, L. Peters, A. A. Titov, et al. 2021. Lupus susceptibility gene Esrrg modulates
J. N. Glickman, and W. S. Garrett. 2013. The microbial metabolites, short-chain fatty regulatory T cells through mitochondrial metabolism. JCI Insight 6: e143540.
acids, regulate colonic Treg cell homeostasis. Science 341: 569573. 55. Battaglia, M., A. Stabilini, B. Migliavacca, J. Horejs-Hoeck, T. Kaupper, and
27. Arpaia, N., C. Campbell, X. Fan, S. Dikiy, J. van der Veeken, P. deRoos, H. Liu, M. G. Roncarolo. 2006. Rapamycin promotes expansion of functional CD41
J. R. Cross, K. Pfeffer, P. J. Coffer, and A. Y. Rudensky. 2013. Metabolites produced CD251FOXP31 regulatory T cells of both healthy subjects and type 1 diabetic
by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504: patients. J. Immunol. 177: 83388347.
451455. 56. He, S., Y. Zhang, D. Wang, K. Tao, S. Zhang, L. Wei, and Q. Chen. 2016.
28. Munn, D. H., and A. L. Mellor. 2016. IDO in the tumor microenvironment: Rapamycin/GABA combination treatment ameliorates diabetes in NOD mice. Mol.
inflammation, counter-regulation, and tolerance. Trends Immunol. 37: 193207. Immunol. 73: 130137.
29. Carbone, F., V. De Rosa, P. B. Carrieri, S. Montella, D. Bruzzese, A. Porcellini, 57. Monti, P., M. Scirpoli, P. Maffi, L. Piemonti, A. Secchi, E. Bonifacio, M. G. Roncarolo,
C. Procaccini, A. La Cava, and G. Matarese. 2014. Regulatory T cell proliferative and M. Battaglia. 2008. Rapamycin monotherapy in patients with type 1 diabetes modi-
potential is impaired in human autoimmune disease. Nat. Med. 20: 6974. fies CD41CD251FOXP31 regulatory T-cells. Diabetes 57: 23412347.
30. Matarese, G., P. B. Carrieri, A. La Cava, F. Perna, V. Sanna, V. De Rosa, D. Aufiero, 58. Long, S. A., M. Rieck, S. Sanda, J. B. Bollyky, P. L. Samuels, R. Goland,
S. Fontana, and S. Zappacosta. 2005. Leptin increase in multiple sclerosis associates A. Ahmann, A. Rabinovitch, S. Aggarwal, D. Phippard, et al.; Diabetes TrialNet
with reduced number of CD41CD251 regulatory T cells. Proc. Natl. Acad. Sci. USA and the Immune Tolerance Network. 2012. Rapamycin/IL-2 combination therapy in
102: 51505155. patients with type 1 diabetes augments Tregs yet transiently impairs b-cell function.
31. Esposito, M., F. Ruffini, M. Bellone, N. Gagliani, M. Battaglia, G. Martino, and Diabetes 61: 23402348.
R. Furlan. 2010. Rapamycin inhibits relapsing experimental autoimmune encepha- 59. Koprivica, I., M. Vujičić, D. Gajić, T. Saksida, and I. Stojanović. 2018. Ethyl pyruvate
lomyelitis by both effector and regulatory T cells modulation. J. Neuroimmunol. stimulates regulatory T cells and ameliorates type 1 diabetes development in mice.
220: 5263. Front. Immunol. 9: 3130.
1866 BRIEF REVIEWS: TREG CELL METABOLISM IN AUTOIMMUNITY

60. Zhang, D., C. Chia, X. Jiao, W. Jin, S. Kasagi, R. Wu, J. E. Konkel, H. Nakatsukasa, 66. Sun, Y., T. Tian, J. Gao, X. Liu, H. Hou, R. Cao, B. Li, M. Quan, and L. Guo. 2016.
P. Zanvit, N. Goldberg, et al. 2017. D-mannose induces regulatory T cells and sup- Metformin ameliorates the development of experimental autoimmune encephalomyelitis
presses immunopathology. Nat. Med. 23: 10361045. by regulating T helper 17 and regulatory T cells in mice. J. Neuroimmunol. 292: 5867.
61. Huang, S. H., S. L. Kuo, S. J. Chen, J. R. Lin, Y. W. Chen, Z. J. Hong, H. K. Sytwu, 67. Aso, K., M. Kono, M. Kanda, Y. Kudo, K. Sakiyama, R. Hisada, K. Karino, Y. Ueda,
and G. J. Lin. 2022. Alpha-lipoic acid inhibits spontaneous diabetes and autoimmune D. Nakazawa, Y. Fujieda, et al. 2023. Itaconate ameliorates autoimmunity by modulating
recurrence in non-obese diabetic mice by enhancing differentiation of regulatory T cells T cell imbalance via metabolic and epigenetic reprogramming. Nat. Commun. 14: 984.
and showed potential for use in cell therapies for the treatment of type 1 diabetes. Int. J. 68. Lai, Z. W., R. Hanczko, E. Bonilla, T. N. Caza, B. Clair, A. Bartos, G. Miklossy,
Mol. Sci. 23: 1169. J. Jimah, E. Doherty, H. Tily, et al. 2012. N-acetylcysteine reduces disease activity
62. Jacob, N., S. Jaiswal, D. Maheshwari, N. Nallabelli, N. Khatri, A. Bhatia, A. Bal, by blocking mammalian target of rapamycin in T cells from systemic lupus erythe-
V. Malik, S. Verma, R. Kumar, and N. Sachdeva. 2020. Butyrate induced Tregs matosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis
are capable of migration from the GALT to the pancreas to restore immunological Rheum. 64: 29372946.
tolerance during type-1 diabetes. Sci. Rep. 10: 19120. 69. Gu, Z., W. Tan, J. Ji, G. Feng, Y. Meng, Z. Da, G. Guo, Y. Xia, X. Zhu, G. Shi,
63. de Candia, P., C. Procaccini, C. Russo, M. T. Lepore, and G. Matarese. 2022. Regula- and C. Cheng. 2016. Rapamycin reverses the senescent phenotype and improves
tory T cells as metabolic sensors. Immunity 55: 19811992. immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic
64. Rena, G., D. G. Hardie, and E. R. Pearson. 2017. The mechanisms of action of lupus erythematosus patients through inhibition of the mTOR signaling pathway.
metformin. Diabetologia 60: 15771585. Aging (Albany NY)) 8: 11021114.
65. Lee, S. Y., S. H. Lee, E. J. Yang, E. K. Kim, J. K. Kim, D. Y. Shin, and M. L. Cho. 70. Lai, Z. W., R. Kelly, T. Winans, I. Marchena, A. Shadakshari, J. Yu, M. Dawood,

Downloaded from http://journals.aai.org/jimmunol/article-pdf/212/12/1859/1657757/ji2400079.pdf by Chulalongkorn Univ Lib/Fac of Med user on 08 June 2024
2015. Metformin ameliorates inflammatory bowel disease by suppression of the R. Garcia, H. Tily, L. Francis, et al. 2018. Sirolimus in patients with clinically active
STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS systemic lupus erythematosus resistant to, or intolerant of, conventional medications:
One 10: e0135858. a single-arm, open-label, phase 1/2 trial. Lancet 391: 11861196.