Eur. J. Immunol. 2016. 46: 2705–2709 DOI: 10.1002/eji.201646663 S. S. Gabriel and A.

Kallies 2705

Basic
HIGHLIGHTS

COMMENTARY
Sugars and fat – A healthy way to generate functional
regulatory T cells
Sarah Sharon Gabriel1,2 and Axel Kallies1,2

1
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2
The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

Cellular metabolism has emerged as an important regulator of adaptive immunity. While

the metabolic requirements of conventional T cells are increasingly understood, the role
of cellular metabolism in Foxp3+ regulatory T (Treg) cells is less clear. Although it is well
accepted that repression of Akt/mTOR, HIF-1α and aerobic glycolysis are important for
the efficient generation of Treg cells in vitro, clear evidence how these pathways impact
on Treg-cell development in vivo is limited. Furthermore, newer studies have shown
that the same pathways that appear to suppress Treg-cell development are active in
and required for functionally mature Treg cells. Thus, it becomes increasingly evident
that development and function of regulatory T cells require different wiring of metabolic
pathways. Finally, it is likely that critical differences remain to be uncovered between
the metabolism of resting or ‘naı̈ve’ Treg cells and those fully differentiated and actively
engaged in suppression. In this comment, we briefly discuss our current understanding
of Treg-cell metabolism and the need to address this area with new approaches based on
in vivo models.

Keywords: Metabolism r Molecular immunology r Regulatory T cells r T cells

See accompanying articles by Petzold et al. and Dimeloe et al.

T-cell differentiation and function are tightly coordinated with lized in the tricarboxylic acid (TCA) cycle, together with other
cellular metabolism, and multiple pathways link the molecular substrates such as fatty acids (FA) via β-oxidation (also called
control of both processes. As T cells differentiate into effector fatty acid oxidation FAO). Ultimately, the reducing equivalents
or memory cells in response to antigen-receptor stimulation and produced in the TCA cycle fuel ATP production via OXPHOS [1].
cytokines, their cellular metabolism undergoes profound changes Upon activation, T-cell metabolism undergoes dramatic changes
in order to adapt to novel requirements. However, at the same in order to meet the high energy demands associated with the
time non-immunological cues such as availability of nutrients, oxy- proliferative burst and effector molecule production. Similar to
gen tension or the accumulation of metabolites influence cellular highly proliferative cancer cells, activated T cells switch to aerobic
metabolism and thereby affect the activity and fate of T cells. glycolysis, which is less efficient for ATP production, but generates
Naı̈ve T cells display a low energy demand and derive their precursor molecules for the generation of lipids, amino acids and
energy mainly through the highly efficient process of oxidative nucleotides needed for rapid proliferation [1].
phosphorylation (OXPHOS). Low-level glycolytic activity yields T-cell metabolism is coordinated by a complex network of
pyruvate, which is imported into the mitochondria and metabo- conserved signaling pathways involving the mammalian target
of rapamycin (mTOR), AMP-activated protein kinase (AMPK),
and the transcription factors hypoxia-inducible factor 1α (HIF-
Correspondence: Dr. Axel Kallies
1α) and MYC. mTOR is activated rapidly in response to TCR lig-
e-mail: [email protected] ation and costimulation and its activity is further modulated by


C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu
2706 S. S. Gabriel and A. Kallies Eur. J. Immunol. 2016. 46: 2705–2709

cial for T helper (Th)-cell differentiation, Treg cells rely largely

on AMPK-promoted mitochondrial FAO [9–11]. This model is
supported by various studies showing that genetic or pharma-
cological interventions that modulate either metabolic arm affect
Th-cell and Treg-cell differentiation in an opposing fashion. In
particular, blockade of FAO was shown to preclude the genera-
tion of Treg cells, while stimulation of this pathway, either by
adding exogenous FA or by pharmacological activation of AMPK,
promoted Treg-cell generation [9]. On the other hand, inhibi-
tion of glycolysis resulted in preferential Treg-cell generation, as
shown by the pharmacological blockade of mTOR activity, or by
the genetic deletion of mTOR or HIF-1α [9, 10, 12]. In contrast,
constitutive active Akt/mTOR signaling promoted Th-cell gener-
Figure 1. mTOR activity balances Treg cell development and function.
Low mTOR activity translates into low-level glycolysis and preferen- ation [11]. Interestingly, FA metabolism appears to differently
tial energy production through oxidative phosphorylation (OXPHOS) regulated between Th cells and Treg cells; for example, de novo
and fatty acid oxidation (FAO) in mitochondria. This metabolic state FA synthesis is only required for Th-cell but not Treg-cell differ-
is associated with successful generation of Treg cells as demonstrated
by increased Treg-cell development upon rapamycin treatment and entiation [13]. Together, these results have created a paradigm
AMPK activation. In contrast, high mTOR activity, HIF-1α and rewiring according to which the activation of anabolic pathways linked to
of cellular metabolism toward aerobic glycolysis inhibits Treg-cell gen- aerobic glycolysis is crucial for successful CD4+ effector cell dif-
eration, but is required for suppressive function of Treg cells. mTOR
also contributes to Treg-cell homeostasis and suppressive function via ferentiation and expansion, whereas the same pathways seem to
promotion of lipid and cholesterol biosynthesis from glucose. However, be redundant or even inhibitory for Treg-cell differentiation.
Treg-cell-specific restraint of mTOR activity via the phosphatase PP2A However, an important caveat of the aforementioned studies is
is required, as mTOR hyper activation results in functional failure and
Treg-cell instability. the fact that the vast majority of findings were derived from in vitro
experiments, where naı̈ve CD4+ cells were stimulated under Th-
or Treg-polarizing conditions. This raises the question of: To what
metabolic and environmental cues, such as glucose and essen- degree do these findings represent the in vivo reality? Do in vitro-
tial amino acid availability or growth factors [2]. Once activated, induced (i) Treg cells correctly represent the metabolic phenotypes
mTOR plays a central role in rewiring cellular metabolism toward and requirements of Treg cells that occur in vivo? Do thymically
aerobic glycolysis and in promoting cell growth, proliferation and derived (t)Treg cells and peripherally induced (p)Treg cells show
migration [2, 3] (Fig. 1). mTOR exists in the form of two pro- differences in their utilization of metabolic pathways? During in
tein complexes, mTORC1 and mTORC1, with mTORC1 being vitro iTreg-cell differentiation, cells are routinely exposed to high
the main target of rapamycin. HIF-1α and MYC are activated in concentrations of TGF-β, which is known to be involved in regu-
response to TCR stimulation and promote the expression of genes lating various biological processes, including cell growth, prolif-
needed for efficient glycolysis [4, 5]. In contrast, AMPK is acti- eration, and cellular metabolism by inhibiting the Akt/mTOR axis
vated in response to stress and decreased cellular ATP levels and [12, 14, 15]. Thus, the dampened cellular metabolism observed
promotes pathways that conserve energy. As such, AMPK counter- in iTreg cells might be an indirect consequence prolonged TGF-
acts anabolic pathways in activated T cells such as FA synthesis by β exposure rather than a requirement for iTreg-cell generation.
inhibiting mTORC1 activity, and instead promotes energy-efficient Notably, genetic loss of mTOR results in hyperactivation of Smad3,
ATP production through OXPHOS and mitochondrial FAO [5] which is downstream of TGF-β signaling [12] and required for
(Fig. 1). iTreg-cell induction [14, 16]. Thus, increased Treg-cell genera-
Treg cells are a specialized lineage of CD4+ T cells that can tion in response to mTOR blockade may also be a consequence of
efficiently suppress immune responses to self and foreign antigen. ectopic activation of Smad3, rather than due to a reduction in aer-
Treg cells also fulfill critical functions in tissue repair, homeosta- obic glycolysis. However, so far it has not been stringently tested
sis and limiting metabolic diseases. Functional impairments of whether dampening of the Akt/mTOR axis is critical for the in vivo
Treg cells have been shown to result in autoimmunity, and the generation of pTreg cells. Similarly, it is unclear which metabolic
loss of Treg cells leads to fatal immunopathology in both humans pathways are essential for the thymic generation of Treg cells,
and mice [6, 7]. The vast majority of Treg cells develop in the although one study has suggested that receptor S1P1-mediated
thymus in a TCR- and IL-2-dependent manner. A smaller propor- activation of mTOR plays a limiting role [17]. In this context, a
tion of Treg cells is induced in the periphery, in particular in the FoxP3 double-reporter mouse, which allows the discrimination of
gastrointestinal tract, in response to microbiota-derived antigens thymically and peripherally derived Treg cells, might prove to be a
and metabolites, such as short-chain FA [8]. Based on a large useful tool [18]. The basis for this mouse model is the observation
body of evidence, Treg cells are believed to display very distinct that a Foxp3-green fluorescence (GFP) transgene [19] is only acti-
metabolic requirements compared to their effector T-cell coun- vated during thymic Treg-cell development, but not during differ-
terparts. Analysis of in vitro polarized CD4+ cells suggested that entiation of Foxp3+ Treg cells in vitro or in the periphery of mice.
while Akt/mTOR- and HIF-1α-mediated aerobic glycolysis is cru- Thus, combination of the Foxp3-GFP transgene with a Foxp3-red


C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu
Eur. J. Immunol. 2016. 46: 2705–2709 HIGHLIGHTS 2707

fluorescence (RFP) knock-in allele [20] that faithfully reports Treg cells, which previously were thought to be negligible in in
Foxp3 expression in both tTreg and pTreg cells, results in a vitro-generated Treg cells.
Foxp3 double reporter, in which pTreg cells are RFP+GFP-, while When analyzing metabolism of Treg cells, it is important to note
tTreg cells are positive for both RFP and GFP [18]. Notably, the that in vivo-occurring Treg cells do not represent a homogenous
authors show that other molecules currently considered to be population. In addition to the above-mentioned discrimination of
expressed specifically on thymically derived Treg cells, including Treg cells based on their developmental origin, Treg cells display
Nrlp1 [21, 22] and Helios [8], were expressed similarly in Foxp3+ different activation states, which are likely to result in different
GFP− and GFP+ Treg cells [18], suggesting that these surrogate metabolic activity. Broadly, Treg cells can be divided into central
markers of tTreg cells should be treated with caution. However, (c)Treg cells, which mainly recirculate through lymphoid tissues
additional experiments should be performed to fully characterize and show a naı̈ve phenotype, and effector (e)Treg cells, which
the double reporter mouse model, including a detailed analysis accumulate in non-lymphoid tissues and display high expression
of the colonic Treg-cell compartment. Furthermore, it should be of activation markers and the transcription factor Blimp-1. Most
attempted to reconcile the apparent lack of correlation between importantly, eTreg cells show superior suppressive activity, and
the phenotypes of pTreg identified based on Nrlp1 or Helios with secretion of the immune suppressive cytokine IL-10 is limited to
those identified using the Foxp3 double reporter. Nevertheless, eTreg cells [33, 34]. Notably, eTreg cells can functionally adapt to
new mouse models and experimental strategies are required to their local environment to exert tissue-specific functions [35]. For
thoroughly dissect the impact of metabolic pathways on Treg-cell example, Treg cells found in the visceral adipose tissue express the
development both in the thymus and in the periphery. transcription factor PPARγ, which induces an increased expression
In addition to the limitations of our current understanding of of genes associated with lipid metabolism, such as enzymes for FA
the metabolic requirements of Treg-cell development discussed synthesis, oxidation and transport [36]. It is technically challeng-
above, there are other reasons why the prevailing model of a ing to characterize the metabolism of various Treg-cell subsets ex
“metabolic Treg-Th cell dichotomy” should be revisited. Recent vivo, as these cells are rare and their isolation requires a combi-
studies analyzing the metabolic profile of naturally occurring Treg nation of surface markers and reporters for lineage-defining tran-
cells directly after ex vivo isolation are difficult to reconcile with scription factors. In this regard, a Blimp-1/Foxp3 double-reporter
the idea that Treg cells do not depend on aerobic glycolysis. mouse that allows isolation of eTreg-cell subsets may provide a
For example, cycling Treg cells display increased Glut1 expres- useful tool [37]. Thus, when examining the impact of metabolic
sion and activation of mTORC1 [23], and in comparison to any pathways on Treg-cell biology, it is essential to consider the differ-
other cell type, including tumor-infiltrating CD4+ T cells, splenic, ent origin and activation status of Treg-cell populations and their
and intratumoral Treg cells display higher glycolytic activity [24], effector counterpart.
a hallmark of proliferating cells. Indeed, Treg cells consistently Finally, a detailed understanding of the molecular differences
display high turnover, probably in response to self-antigen stim- between Treg cells and their conventional counterparts is required
ulation [25–27]. These findings are in line with a comprehen- to fully unravel Treg-cell-specific metabolic requirements. For
sive study comparing the metabolic profiles of ex vivo isolated example, it has been shown by Dimeloe et al. that various CD4+
human Treg cells and conventional T cells. At steady state, Treg T-cell populations express different amounts of the multidrug
cells showed increased activity of mTOR and expression of pro- resistance protein ABCB1, also called P-glycoprotein, encoded
teins associated with the glycolytic pathway and lipid synthe- by multidrug resistant gene 1 [38]. While Treg cells appear to
sis, a significantly higher glycolytic flux, but reduced expression lack expression of ABCB1, the bulk of CD4+ and CD8+ T cells,
of components of the TCA cycle as compared to conventional including central and effector memory cells, express this efflux
T cells [26, 28] (Fig. 1). Furthermore, several studies indicate that pump [38, 39]. Notably, mitotracker green, which is a commonly
important promotors of glycolytic activity are needed for Treg-cell used stain to determine mitochondrial mass, is a substrate for
suppressive function in vivo. For example, Treg cells lacking HIF- ABCB1. Therefore, caution is required when interpreting results
1α or mTORC1 fail to control T-cell-mediated colitis [29, 30]. based on mitochondrial stains in various T cells subsets and in
mTORC1 signaling has been shown to be constitutively active in particular in Treg cells.
Treg cells and to be required for proliferation and suppressive In summary, new approaches are required to unravel the
function, as genetic loss of mTORC1 in specifically in Treg cells metabolic regulation of Treg-cell development and function. These
resulted in fatal autoimmune disease similar to the scurfy pheno- approaches need to take into consideration the potential dif-
type [30] (Fig. 1). Specifically, mTORC1 was found to be essential ferences in metabolism in Treg-cell subpopulations based on
for Treg-cell homeostasis and suppressive function via promotion their developmental origin as well as the distinct maturation
of lipid and cholesterol biosynthesis from glucose [30] (Fig. 1). stages of Treg cells in the periphery. Thorough understanding
On the other side, unrestrained Akt/mTOR activity, due to loss the metabolism of Treg cells offer novel pharmacological targets
of negative regulators such PP2A and PTEN, has been shown to for the specific promotion or inhibition of Treg-cell development
impair Treg-cell stability and suppressive function, suggesting that and function. In order to meet this goal, we have to combine our
close control of mTOR activity in vivo is required [31, 32]. Thus, advanced understanding of in vivo Treg-cell biology with the field
in vivo studies reveal the importance of metabolic regulators in of immunometabolism.


C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu
2708 S. S. Gabriel and A. Kallies Eur. J. Immunol. 2016. 46: 2705–2709

15 Delisle, J. S., Giroux, M., Boucher, G., Landry, J. R., Hardy, M. P., Lemieux,
S., Jones, R. G. et al., The TGF-beta-Smad3 pathway inhibits CD28-
dependent cell growth and proliferation of CD4 T cells. Genes Immun.
2013. 14: 115–126.

Acknowledgments: We wish to thank the members of the 16 Li, L., Iwamoto, Y., Berezovskaya, A. and Boussiotis, V. A., A pathway

Kallies lab for discussion. This work was supported by fellowships regulated by cell cycle inhibitor p27Kip1 and checkpoint inhibitor Smad3
is involved in the induction of T cell tolerance. Nat. Immunol. 2006. 7:
from the Sylvia and Charles Viertel Foundation (Senior Medical
1157–1165.
Research Fellowship to A.K.) and the Swiss National Science Foun-
17 Liu, G., Burns, S., Huang, G., Boyd, K., Proia, R. L., Flavell, R. A., and
dation (Postdoctoral fellowship to S.G.).
Chi, H., The receptor S1P1 overrides regulatory T cell-mediated immune
suppression through Akt-mTOR. Nat. Immunol. 2009. 10: 769–777.

18 Petzold, C., Steinbronn, N., Gereke, M., Strasser, R. H., Sparwasser, T.,
Conflict of interest: The authors declare no financial or commer- Bruder, D., Geffers, R. et al., Fluorochrome-based definition of naturally
cial conflict of interest. occurring Foxp3(+) regulatory T cells of intra- and extrathymic origin.
Eur. J. Immunol. 2014. 44: 3632–3645.

19 Zhou, X., Jeker, L. T., Fife, B. T., Zhu, S., Anderson, M. S., McManus,
References M. T., and Bluestone, J. A., Selective miRNA disruption in T reg cells
leads to uncontrolled autoimmunity. J. Exp. Med. 2008. 205: 1983–
1 Buck, M. D., O’Sullivan, D. and Pearce, E. L., T cell metabolism drives 1991.
immunity. J. Exp. Med. 2015. 212: 1345–1360. 20 Wan, Y. Y. and Flavell, R. A., Identifying Foxp3-expressing suppressor
2 Chi, H., Regulation and function of mTOR signalling in T cell fate deci- T cells with a bicistronic reporter. Proc. Natl. Acad. Sci. USA 2005. 102:
sions. Nat. Rev. Immunol. 2012. 12: 325–338. 5126–5131.

3 Pollizzi, K. N. and Powell, J. D., Integrating canonical and metabolic 21 Weiss, J. M., Bilate, A. M., Gobert, M., Ding, Y., Curotto de Lafaille, M. A.,
signalling programmes in the regulation of T cell responses. Nat. Rev. Parkhurst, C. N., Xiong, H. et al., Neuropilin 1 is expressed on thymus-
Immunol. 2014. 14: 435–446. derived natural regulatory T cells, but not mucosa-generated induced
Foxp3+ T reg cells. J. Exp. Med. 2012. 209: 1723–1742, S1.
4 Wang, R., Dillon, C. P., Shi, L. Z., Milasta, S., Carter, R., Finkelstein, D.,
McCormick, L. L. et al., The transcription factor Myc controls metabolic 22 Yadav, M., Louvet, C., Davini, D., Gardner, J. M., Martinez-Llordella, M.,
reprogramming upon T lymphocyte activation. Immunity 2011. 35: 871– Bailey-Bucktrout, S., Anthony, B. A. et al., Neuropilin-1 distinguishes
882. natural and inducible regulatory T cells among regulatory T cell subsets
in vivo. J. Exp. Med. 2012. 209: 1713–1722, S1–S19.
5 Johnson, M. O., Siska, P. J., Contreras, D. C. and Rathmell, J. C., Nutrients
and the microenvironment to feed a T cell army. Semin. Immunol. 2016. 23 Gerriets, V. A., Kishton, R. J., Johnson, M. O., Cohen, S., Siska, P. J.,
Epub ahead of print. Nichols, A. G., Warmoes, M. O. et al., Foxp3 and Toll-like receptor signal-
ing balance Treg cell anabolic metabolism for suppression. Nat. Immunol.
6 Burzyn, D., Benoist, C. and Mathis, D., Regulatory T cells in nonlymphoid
2016. Epub ahead of print.
tissues. Nat. Immunol. 2013. 14: 1007–1013.
24 Ho, P. C., Bihuniak, J. D., Macintyre, A. N., Staron, M., Liu, X., Amezquita,
7 Ohkura, N., Kitagawa, Y. and Sakaguchi, S., Development and mainte-
R., Tsui, Y. C. et al., Phosphoenolpyruvate is a metabolic checkpoint of
nance of regulatory T cells. Immunity 2013. 38: 414–423.
anti-tumor T cell responses. Cell 2015. 162: 1217–1228.
8 Tanoue, T., Atarashi, K. and Honda, K., Development and maintenance
25 Fisson, S., Darrasse-Jeze, G., Litvinova, E., Septier, F., Klatzmann, D.,
of intestinal regulatory T cells. Nat. Rev. Immunol. 2016. 16: 295–309.
Liblau, R., and Salomon, B. L., Continuous activation of autoreactive
9 Michalek, R. D., Gerriets, V. A., Jacobs, S. R., Macintyre, A. N., MacIver, CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 2003. 198:
N. J., Mason, E. F., Sullivan, S. A. et al., Cutting edge: distinct glycolytic 737–746.
and lipid oxidative metabolic programs are essential for effector and
26 Procaccini, C., Carbone, F., Di Silvestre, D., Brambilla, F., De Rosa, V., Gal-
regulatory CD4+ T cell subsets. J. Immunol. 2011. 186: 3299–3303.
gani, M., Faicchia, D. et al., The proteomic landscape of human ex vivo
10 Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., and Chi, regulatory and conventional T cells reveals specific metabolic require-
H., HIF1alpha-dependent glycolytic pathway orchestrates a metabolic ments. Immunity 2016. 44: 406–421.
checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med.
27 Pierson, W., Cauwe, B., Policheni, A., Schlenner, S. M., Franckaert, D.,
2011. 208: 1367–1376.
Berges, J., Humblet-Baron, S. et al., Antiapoptotic Mcl-1 is critical for the
11 Haxhinasto, S., Mathis, D. and Benoist, C., The AKT-mTOR axis regulates survival and niche-filling capacity of Foxp3(+) regulatory T cells. Nat.
de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 2008. 205: 565– Immunol. 2013. 14: 959–965.
574.
28 Procaccini, C., De Rosa, V., Galgani, M., Abanni, L., Cali, G., Porcellini,
12 Delgoffe, G. M., Kole, T. P., Zheng, Y., Zarek, P. E., Matthews, K. L., Xiao, A., Carbone, F. et al., An oscillatory switch in mTOR kinase activity sets
B., and Worley, P. F., The mTOR kinase differentially regulates effector regulatory T cell responsiveness. Immunity 2010. 33: 929–941.
and regulatory T cell lineage commitment. Immunity 2009. 30: 832–844.
29 Clambey, E. T., McNamee, E. N., Westrich, J. A., Glover, L. E., Campbell,
13 Berod, L., Friedrich, C., Nandan, A., Freitag, J., Hagemann, S., Harmrolfs, E. L., Jedlicka, P., de Zoeten, E. F. et al., Hypoxia-inducible factor-1 alpha-
K., Sandouk, A. et al., De novo fatty acid synthesis controls the fate dependent induction of FoxP3 drives regulatory T-cell abundance and
between regulatory T and T helper 17 cells. Nat. Med. 2014. 20: 1327–1333. function during inflammatory hypoxia of the mucosa. Proc. Natl. Acad.
14 Martinez, G. J., Zhang, Z., Chung, Y., Reynolds, J. M., Lin, X., Jetten, A. Sci. USA 2012. 109: E2784–E2793.
M., Feng, X. H. et al., Smad3 differentially regulates the induction of 30 Zeng, H., Yang, K., Cloer, C., Neale, G., Vogel, P. and Chi, H., mTORC1
regulatory and inflammatory T cell differentiation. J. Biol. Chem. 2009. couples immune signals and metabolic programming to establish T(reg)-
284: 35283–35286. cell function. Nature 2013. 499: 485–490.


C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu
Eur. J. Immunol. 2016. 46: 2705–2709 HIGHLIGHTS 2709

31 Apostolidis, S. A., Rodriguez-Rodriguez, N., Suarez-Fueyo, A., Dioufa, cyclophosphamide-extruding transporter ABCB1 and are more suscep-
N., Ozcan, E., Crispin, J. C., Tsokos, M. G. et al., Phosphatase PP2A is tible to cyclophosphamide-induced apoptosis. Eur. J. Immunol. 2014. 44:
requisite for the function of regulatory T cells. Nat. Immunol. 2016. 17: 556– 3614–3620.
564.
39 Drach, D., Zhao, S., Drach, J., Mahadevia, R., Gattringer, C., Huber, H.,
32 Huynh, A., DuPage, M., Priyadharshini, B., Sage, P. T., Quiros, J., Borges, Andreeff, M. et al., Subpopulations of normal peripheral blood and bone
C. M., Townamchai, N. et al., Control of PI(3) kinase in Treg cells main- marrow cells express a functional multidrug resistant phenotype. Blood
tains homeostasis and lineage stability. Nat. Immunol. 2015. 16: 188–196. 1992. 80: 2729–2734.

33 Teh, P. P., Vasanthakumar, A. and Kallies, A., Development and function

of effector regulatory T cells. Prog. Mol. Biol. Transl. Sci. 2015. 136: 155–174. Abbreviations: AMPK: AMP-activated protein kinase · FA: fatty acid ·
34 Cretney, E., Xin, A., Shi, W., Minnich, M., Masson, F., Miasari, M., Belz, FAO: fatty acid oxidation · GFP: green fluorescence · HIF-1a: hypoxia-
G. T. et al., The transcription factors Blimp-1 and IRF4 jointly control the inducible factor 1a · mTOR: mammalian target of rapamycin · OXPHOS:
differentiation and function of effector regulatory T cells. Nat. Immunol.
oxidative phosphorylation · RFP: red fluorescence · TCA: tricarboxylic
2011. 12: 304–311.
acid · Th: T helper cell · Treg: regulatory T cell
35 Panduro, M., Benoist, C. and Mathis, D., Tissue Tregs. Annu. Rev. Immunol.
2016. 34: 609–633.
Full correspondence: Dr. Axel Kallies, The Walter and Eliza Hall Institute
36 Cipolletta, D., Feuerer, M., Li, A., Kamei, N., Lee, J., Shoelson, S. E., of Medical Research, 1G Royal Parade, Parkville VIC 3052, Australia
Benoist, C. et al., PPAR-gamma is a major driver of the accumula- e-mail: [email protected]
tion and phenotype of adipose tissue Treg cells. Nature 2012. 486: 549–
553.
See accompanying article:
37 Vasanthakumar, A., Moro, K., Xin, A., Liao, Y., Gloury, R., Kawamoto, http://dx.doi.org/10.1002/eji.201444750
S., Fagarasan, S. et al., The transcriptional regulators IRF4, BATF and IL- http://dx.doi.org/10.1002/eji.201444879
33 orchestrate development and maintenance of adipose tissue-resident
regulatory T cells. Nat. Immunol. 2015. 16: 276–285.
Received: 2/11/2016
38 Dimeloe, S., Frick, C., Fischer, M., Gubser, P. M., Razik, L., Ban- Revised: 2/11/2016
tug, G. R., Ravon, M. et al., Human regulatory T cells lack the Accepted: 8/11/2016


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