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Immunological Reviews.2020;00:114.| immune system is mainly responsible for protecting individu-als from pathogen invasion.Meanwhile,the immune system also actively participates in tissue repairing and homeostasis,which are critical for the avoidance of autoimmunity.A subset of CD4+T cells,which is characterized by the expression of the master transcription factor forkhead box protein P3(Foxp3)and known as regulatory T cells(Tregs),is the major immune subset to maintain the immune ho-meostasis.1-4 The importance of Tregs on governing peripheral tissue and immune homeostasis is validated by observations in both human patients and murine models.In humans,the mutations in Foxp3 re-sult in impaired development and dysfunction of Tregs and cause im-mune dysregulation polyendocrinopathy enteropathy X-linked(IPEX)syndrome,characterized by multiple autoimmune disorders.5,6 Mice carrying dysfunctional Foxp3,known as scurfy mice,are deficient in Received:29 January 2020|Accepted:19 February 2020DOI:10.1111/imr.12844 I N V I T E D R E V I E WMetabolic adaptation orchestrates tissue context-dependent behavior in regulatory T cellsHaiping Wang1,2|Chun-Hao Lu1,2|Ping-Chih Ho1,2 2020 John Wiley&Sons A/S.Published by John Wiley&Sons LtdThis article is part of a series of reviews covering Metabolic Alterations in Immune Cells appearing in Volume 295 of Immunological Reviews.1Department of Fundamental Oncology,University of Lausanne,Lausanne,Switzerland2Ludwig Institute for Cancer Research,University of Lausanne,Epalinges,SwitzerlandCorrespondenceHaiping Wang;Ping-Chih Ho,Department of Fundamental Oncology,Ludwig Institute for Cancer Research,University of Lausanne,Chemin des Boveresses 155,1066 Epalinges,Switzerland.Email:haiping.wangunil.ch;ping-chih.hounil.chFunding informationH2020 European Research Council,Grant/Award Number:ISREC 26075483;Swiss Institute for Experimental Cancer Research,Grant/Award Number:ISREC 26075483;SNSF project grants,Grant/Award Number:31003A_182470AbstractThe diverse distribution and functions of regulatory T cells(Tregs)ensure tissue and immune homeostasis;however,it remains unclear which factors can guide distribu-tion,local differentiation,and tissue context-specific behavior in Tregs.Although the emerging concept that Tregs could re-adjust their transcriptome based on their habitations is supported by recent findings,the underlying mechanisms that repro-gram transcriptome in Tregs are unknown.In the past decade,metabolic machineries have been revealed as a new regulatory circuit,known as immunometabolic regula-tion,to orchestrate activation,differentiation,and functions in a variety of immune cells,including Tregs.Given that systemic and local alterations of nutrient availability and metabolite profile associate with perturbation of Treg abundance and functions,it highlights that immunometabolic regulation may be one of the mechanisms that orchestrate tissue context-specific regulation in Tregs.The understanding on how metabolic program instructs Tregs in peripheral tissues not only represents a critical opportunity to delineate a new avenue in Treg biology but also provides a unique window to harness Treg-targeting approaches for treating cancer and autoimmun-ity with minimizing side effects.This review will highlight the metabolic features on guiding Treg formation and function in a disease-oriented perspective and aim to pave the foundation for future studies.K E Y W O R D Sautoimmunity,cancer,immunometabolism,inflammation,metabolic adaptation,regulatory T cell2|WANG et Al.Tregs and develop fatal systemic autoimmunity.6 The development of Tregs can be classified according to the sites where they develop.Thymus-derived Tregs(tTregs)are differentiated in the thymus rep-resenting a functionally mature T-cell subset.The differentiation of tTregs depends on the high-affinity interaction of their T-cell receptor(TCR)with specific self-antigen peptide and MHC class II complexes expressed by thymic antigen-presenting cells(APCs).7,8 Upon binding to self-antigen peptide-MCH complexes,the high avidity TCR signal results in the upregulation of CD25(interleukin(IL)-2 receptor chain)forming the high-affinity IL-2 receptor.A subsequent response of Treg precursor cells to IL-2 signals,through signal transducer and activator of transcription 5(STAT5),leads to the expression of Foxp3.9 STAT5 binds directly to cis elements in the Foxp3 promoter and enhancer regions,such as conserved non-coding sequence 2(CNS2),resulting in stable Foxp3 expression.The CNS2,also known as Treg-specific demethylation region(TSDR),is necessary for the lineage stability of proliferating Tregs.10,11 The Ten-eleven translocation(TET)enzyme family is essential for demethylating the CNS regions.12 Deficient ex-pression of Tet2/Tet3 specifically in Tregs led to the loss of Foxp3 expression in Tregs,and the CD4+Foxp3+Tregs showed strong skew-ing toward effector T cells.13,14 In addition to TCR signal,CD28 is also critical to the generation of tTregs.Both CD28-deficient and CD80/CD86-deficient mice have a reduced number of Tregs.15,16 CD28-mediated signal has been shown to reinforce the commitment of Treg lineage by inducing epigenetic and additional differentiation events in the Treg precursor cells.17,18 Therefore,both Foxp3 expression and Treg-specific epigenomic changes are essential for tTreg lineage commitment(Figure 1).In addition to tTregs,naive CD4+T cells can acquire Foxp3+expression in the periphery tissues,known as periph-eral Tregs(pTregs),when they encounter conditions of high amounts of transforming growth factor(TGF)-and retinoic acid in the envi-ronment or responding to metabolites produced by microbiota.19,20 Unlike that tTregs mainly recognize self-antigens,the TCR repertoire of pTregs also includes TCRs in response to nonself-antigens derived from allergens,food,and infectious agents or innocuous commensal microbiota,which are important for the maintenance of mucosal tol-erance.21 So far,definitive markers differentiating tTreg from pTreg are still absent and the relative contributions of tTregs and pTregs to tissue homeostasis and inflammatory responses have not been fully determined.Furthermore,the works in the past decade revealed the robust differences on functions,behavior,and transcriptome in Tregs residing in different habitations in the body.Here we will summarize the potential regulations caused by metabolic adaptation and im-munometabolic regulations that orchestrate tissue context-specific behavior of Tregs and how these regulatory circuits will be able to exploit for treating diseases.2|GENERAL FUNCTIONS OF TREGSTregs suppress immune responses via multiple mechanisms.Either they elicit a direct response on a target cell,or a third-party cell or FIGURE 1The development of regulatory T cells.Tregs develop and become mature in both thymus and periphery.In thymus,CD4+CD8+T cells undergo negative selection,in which step they interact with medullary thymic epithelial cells(mTECs),and most autoreactive T cells are eliminated as a result of apoptosis.Nave CD4+T cells with high TCR affinity become mature FoxP3+tTregs in thymus in the presence of cytokines like IL-2 and IL-15,and further commit to stable tTregs by selective demethylation of a conserved element within the Foxp3 locus(TSDR).In the periphery,nave CD4+T cells with low TCR affinity encounter antigens and differentiate into pTregs in the presence of stimuli like TGF-and IL-2,which display unstable FoxP3 expression due to not completed TSDR demethylation.These processes could explain and draw our attention to the stability of FoxP3 in adoptive Treg transfer in treating certain autoimmune diseases|3WANG et Al.molecule is indirectly affected,and in turn,the target cell is sup-pressed.22,23 Tregs can secrete immunosuppressive cytokines such as IL-10,TGF-,and IL-35 or produce perforin and granzyme to inac-tivate or kill the target cells,respectively.22 With the expression of CD39/CD73,they can deplete the microenvironment of extracellular ATP to generate AMP and adenosine leading to the immunosuppres-sion of the target cells.22 Tregs can also deprive IL-2 in the microen-vironment due to their high expression of CD25.The consumption of IL-2 causes survival and metabolic disruption of the target cells.24 A cardinal feature of Tregs is their constitutive expression of the co-inhibitory molecule CTLA-4.25 CTLA-4 binding to CD80/CD86 on APCs results in the induction of indolamine-2,3-dioxygenase(IDO)consuming essential amino acids and hence preventing the prolifera-tion of target cells.26,27 In addition,Tregs binding to APC can lead to stripping of the cell surface molecules affecting co-stimulation and antigen presentation.28 Importantly,many of these suppres-sive mechanisms of Tregs can act without antigen specificity,allow-ing them to suppress effector cells of diverse specificities.29 Tregs can also promote the emergence of other immunosuppressive cell populations,such as Tr1 cells,through the production of immuno-suppressive molecules,a phenomenon called infectious tolerance.30 Among these proposed suppressive mechanisms of Tregs,CTLA-4-dependent and IL-2 consumption-dependent suppression of T-cell activity seems to be a key to Tregs.The pivotal role of CTLA-4 in Treg suppression is illustrated by its deletion in Tregs.Mice lacking CTLA-4 expression by germline deletion or specific loss in Tregs have impaired Treg-mediated immunosuppression and system hy-per-proliferation of T cells,leading to fatal autoimmunity similar to that seen in scurfy mice.31 Its Treg-specific deletion in adult mice also results in spontaneous lymphoproliferation,hypergammaglobu-linemia,and histologically evident autoimmune disorders,which are indicated less severe than those seen in the germline CTLA-4-deficient mice.32,33 Another cardinal feature of Foxp3+Tregs is their constitutive high expression of CD25,which is expressed upon bind-ing of Treg precursor TCR to self-antigen peptide-MCH complexes within the thymus.This Treg-specific immunological property ren-ders Tregs able to quick sense IL-2 produced by self-reactive T cells and co-localize to prevent their further activation,34 thus preventing autoimmunity,a function they serve throughout life.35 IL-2 produced by activated T cells in an active immune response expands Tregs and strengthens their suppressive ability,hence mediating a negative feedback loop.36 High-dose supplementation of IL-2 can neutralize Treg-mediated suppression of T-cell activation and proliferation in vitro.37 Since the discovery of Tregs as a major component of im-mune homeostasis,a precise balance between the immune defense against pathogen invasion and the resolution of immune response to maintain self-tolerance and prevent inflammatory disease,two op-posite clinical applications,autoimmunity and anti-tumor immunity,have been extensively explored.A better understanding of the basic mechanisms of Treg biology is necessary to properly harness Tregs to cure inflammatory diseases or on the contrary to disarm them to tackle cancers,in which,Tregs aberrantly accumulate to suppress anti-tumor immunity in the tumor microenvironment.38-40 Thus,understanding the control of Treg homeostasis and function has sig-nificant therapeutic implications.3|THE DEVELOPMENT AND FUNCTIONS OF TISSUE-RESIDENT TREGSThe emergence of the concept of immune tolerance in the late 1970s was the first step toward the elucidation of Tregs.Nishizuka and Sakakura firstly announced in 1969 that ovarian dysgenesis,an autoimmune disorder,was observed after neonatal thymectomy in mice.41 Followed by more autoimmune responses reported in both mice and humans subjected to thymectomy,42-44 maintenance of T-cell homeostasis was addressed to be responsible for leading im-mune tolerance.Nonetheless,the succeeding studies on Treg deple-tion provided a demonstration of an indispensible role of Tregs in controlling immune tolerance and the development of chronic auto-immune diseases.45-48 The further uncovering of scurfin,the protein product of the transcription factor FoxP3,in mutant scurfy mice,49,50 which presents autoimmune-like disorders,allows the studies to move forward to genetic machineries regarding to immunological homeostasis.Though studies reported the importance of FoxP3 gene transcription in Treg development and its function in both thy-mus and peripheral circulation,51,52 a wide variety of transcription factors or protein regulations accommodating with distinct environ-ments need to be further investigated as one particular therapy for immune tolerance and homeostasis.As mentioned,Tregs are classified into two different subsets.53 One subset forms along thymopoiesis that originates from the differ-entiation of nave T cells upon TCR stimulation or from functionally mature precursors that express CD25(IL-2 receptor chain),resulting in a natural population that is thymus-derived Tregs(tTregs).These Tregs could migrate to the peripheral sites,where they exert their suppressive function.The other subset,which is so-called peripheral induced Tregs(pTregs),is generated in the peripheral lymphoid organs from mature CD4+T cells upon certain antigenic stimulation or in the presence of suppressive cytokines,such as TGF-.The suppressive capacity of this population varies from the local tissue microenvi-ronmental cues and usually directly depends on cytokine production in different disease scenarios.54 After activation,Tregs can further specialized into different effector subsets,such as memory-like and tissue-resident Tregs that play essential roles in non-lymphoid or-gans.55,56 During the past decade,the studies have addressed the underlying mechanisms of Treg compartment differentiation,stabil-ity,and suppression mostly in the thymus and in the periphery.57-59 Only until recently,the presence of Tregs and their potential roles in various non-lymphoid tissues of both mice and humans has been documented,such as bone marrow,skin,intestinal mucosa,lung,liver,adipose tissue,grafts,placenta,muscle,and various tumors.60-66 These tissue-resident Tregs are believed to be significantly differed from Tregs in secondary lymphoid organs since they experience a tissue-specific environment and successively acquire a unique gene expression programing including transcription factors,suppressive 4|WANG et Al.regulatory molecules,homing receptors,and metabolic adaptation.55 The investigation of unique transcriptome and metabolome present-ing by tissue-associated Treg might provide a variety of therapeutic interventions to immunologically mediated disorders by specifically targeting resident Tregs(Figure 2).3.1|Bone marrowBone marrow is known to house the essential pluripotent precursor cells as a soft tissue residing in the cavities of the trabecular bones,primarily consisting of adipocytes and hematopoietic stem cells.67 Though the imperative role of Tregs in modulating the immune system and maintaining self-tolerance