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ScienceDirect Effector T cell differentiation: are master regulators of effector T cells still the masters? Chao Wang, Mary Collins and Vijay K Kuchroo Effector CD4 T cell lineages have been implicated as potent inducers of autoimmune diseases. Tbet, Gata3 and Rorgt are master transcriptional regulators of Th1, Th2 and Th17 lineages respectively and promote the distinct expression of signature cytokines. Significant progress has been made in understanding the transcriptional network that drives CD4 T cell differentiation, revealing novel points of regulation mediated by transcription factors, cell surface receptors, cytokines and chemokines. Epigenetic modifications and metabolic mediators define the transcriptional landscape in which master transcription factors operate and collaborate with a network of transcriptional modifiers to guide lineage specification, plasticity and function. Address Evergrande Center for Immunological Diseases, Harvard Medical School, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA Corresponding author: Kuchroo, Vijay K ([email protected])
Current Opinion in Immunology 2015, 37:6–10 This review comes from a themed issue on Autoimmunity Edited by Mark S Anderson and Fabienne Mackay
http://dx.doi.org/10.1016/j.coi.2015.08.001 0952-7915/Published by Elsevier Ltd.
The helper T cell paradigm introduced by Mosmann and Coffman has been extended to include the well characterized Th1, Th2 and Th17 cell subsets. Naive CD4 T cells acquire lineage specificity by engaging distinct sets of cytokines that activate JAK-STAT-proteins in the context of TCR signals, enabling lineage commitment by the expression of unique master transcription factors Tbet, Gata3 and Rorgt for Th1, Th2 and Th17 cells, respectively. While the importance of the master transcription factors is undisputable, they are clearly not sufficient to define the full extent of effector T cell differentiation and function. Recent studies reveal the complex regulatory network that orchestrates the lineage commitment process of Th17 cells [9,10] and Th2 cells [11]. Th17 cell differentiation is regulated by two opposing transcription network modules that co-exist and antagonize each other, which may, in part, enable the plasticity of the Th17 subset [10]. It is also clear that most transcription factors and other regulators operate only within a transcriptional landscape regulated by higher order epigenetic [12] and metabolic changes that in turn regulate effector CD4 T cell differentiation and function. So how important are master transcription factors in light of these relatively new discoveries affecting gene regulation in Teff cells? This review will focus on recent advances in our understanding of the influence of chromatin structure and cellular metabolism in effector T cell differentiation and function and how these changes can cooperate with master transcription factors and in turn regulate effector T cell lineage commitment.
Regulatory network Introduction Autoreactive T cells are present in both healthy people and in individuals suffering from autoimmune disease [1,2]. In animal models and humans, pathogenic autoreactive effector CD4 T cells (Teff) contribute to autoimmunity by producing cytokines, providing T cell help, provoking direct cellular injury and by recruiting other immune cells to inflammatory sites even in the presence of fully functional regulatory T cells [3–8]. Several lineages of Teff have been described, each with distinct signature cytokines that contribute to autoimmune diseases. Understanding the regulation of Teff lineage commitment and function, and the contribution of Teff to pathology is fundamental in defining novel approaches for the prevention and treatment of autoimmune diseases. Current Opinion in Immunology 2015, 37:6–10
The master regulators were defined as transcription factors that are both necessary and sufficient for the induction of signature cytokines for distinct effector CD4 T cell lineages. As more transcription factors are being discovered, the relative importance of master regulators was questioned [13,14]. For example, the defect in Th17 differentiation in Stat3 deficiency can only be partially rescued by Rorgt overexpression [13]. This is consistent with the finding that the induction of Rorgt is among the second-wave regulators and is necessarily preceded by the expression of pioneering factors such as Stat3, Batf and Irf4 [10]. The timing of Rorgt induction suggests the importance of higher order transcription factors in setting up the chromatin landscape for lineage-specific gene expression and/or for the induction of master regulators themselves. Indeed, cooperatively bound BATF and IRF4 were shown to contribute to initial chromatin accessibility in Th17 cells [9]. Some of these higher www.sciencedirect.com
Are master regulators of Teff cells still the masters? Wang, Collins and Kuchroo 7
order regulators, however, are not specific to a particular T cell lineage. A complete understanding of the T cell differentiation program will depend on appreciation of both the specific set of transcription factors and their hierarchical order, both of which are not yet fully elucidated. It should be appreciated that many transcription factors of the Th17 cell lineage are induced at the same time or after the expression of Rorgt [10]. Indeed, expression of Rorgt is not sufficient to define the transcriptional program for Th17 cells, as functional distinctions in Th17 responses have been defined in response to infection and in autoimmune settings [15,16]. It would be of great interest to decipher the interactions of these regulators with the master transcription factor and to understand how they can cooperatively regulate T cell lineage commitment, function and plasticity.
Epigenetic landscape and regulation of Teff differentiation Similar to the transcriptional network, the epigenetic landscape of effector T cell lineages is characterized in waves. Upon T cell activation, initial histone acetylation occurs in both Th1 and Th2 loci; lineage and locus specific patterns of histone modification only emerge subsequently [12]. Indeed, polarizing cytokines can regulate the epigenetic state of effector CD4 T cells and cause epigenetic changes that are reinforced in a STAT-dependent and master regulator-dependent process [17–19]. The master transcription factors are thought to specify the cytokine pathways that define lineages, however they may not be necessary for regulating the epigenetic status of all signature cytokines. In Th2 cells, Gata3 was shown to be required for DNA demethylation and hyperacetylation of the Il5 gene locus [20]. However, neither Il4 nor Il13 epigenetic marks are regulated by Gata3, suggesting the importance of other regulatory machinery [17,20]. In Th17 cells, histone modification of neither Il17a nor Il17f depends on RORgt and in fact epigenetic modification of very few genes requires RORgt as compared to pioneering transcription factors such as IRF4, BATF and STAT3 [9]. In addition to pioneering transcription factors such IRF4/ BATF for Th17 cells, the epigenetic landscape of effector T cell lineages can be regulated directly by components of histone modification machinery. Mta2, part of a histone deacetylase complex, is found to influence both Th1 and Th2 responses [21]. By performing genome-wide ChIPseq of the histone acyltransferase p300 in Th1, Th2 and Th17 cells, Vahedi et al. identified BACH2 as a crucial regulator of a large set of superenhancer elements shared among T cell lineages [22]. BACH2 deficiency, as compared to STAT, BATF or IRF4, resulted in the largest www.sciencedirect.com
loss of p300 binding to super-enhancer elements that regulate cell identity [22]. This is consistent with BACH2 being a broad suppressor of effector T cell differentiation in Th1, Th2 and Th17 cells [23]. Whereas master transcription factors may not be necessary for all epigenetic changes of signature genes, they can cooperate with epigenetic modifiers and allow selective regulation of gene expression. Indeed, in contrast to BACH2, some epigenetic modifiers can selectively regulate T cell lineages. Mina, a histone demethylase and as well as a ribosomal hydrolase, is identified as a novel positive regulator of Th17 cell differentiation [10]. Jmjd3 is a H3K27 demethylase and Jmjd3 deficiency is found to promote Th2 and Th17, but inhibit Th1 and iTreg cell differentiation [24]. Jmjd3 is also required for plasticity of effector T cells as Th2 or Th17 cells failed to be repolarized into Th1 cells. Interestingly, Jmjd3 is found to interact with Tbet but not Gata3, Foxp3 or Rorgt, providing a potential mechanism for its lineage specificity [24]. Thus epigenetic modifiers can couple with master transcription factors and drive effector T cell lineage commitment. Epigenetics plays a key role in the regulation of autoimmunity by modulating the accessibility of gene loci and transcriptional readiness [25]. Patients with autoimmune diseases were found to have abnormal DNA methylation and histone acetylation in cis-regulatory elements of signature cytokines in CD4 T cells [26–28]. Recent fine-mapping of genome-wide-association studies identified 90% of casual variants as non-coding and largely mapping to immune-cell enhancers [29]. In particular, in CD4 T cells, asthma-associated SNPs are enriched in Th2 cell enhancers [30]. SNPs highly associated with autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and type 1 diabetes, but not other non-autoimmune diseases, showed significantly higher overlap with super-enhancer elements [22]. It remains to be seen how epigenetic modifiers could collaborate with the network of transcription factors and contribute to T cell function.
Metabolic regulation of specific gene expression during Teff differentiation Activation and differentiation of T cells are accompanied by alterations in cellular metabolism. A key question is how these metabolic changes further influence the precise outcome of an immune response. Otto Warburg made the observation in 1958 that leukocytes in response to mitogen opt for a less energy-efficient aerobic glycolysis pathway as compared to oxidative phosphorylation [31], an observation later recapitulated in peripheral T cells [32], alluding to the importance of metabolism beyond the requirement for energy. It was not until 2013 that a specific mechanism was identified: Pearce et al. showed that glycolysis is required to promote T cell effector function by engaging/dis-engaging GAPDH, which Current Opinion in Immunology 2015, 37:6–10
8 Autoimmunity
otherwise binds to the AU-rich element at the 30 end of IFNg and IL-2 mRNA and selectively inhibits their translation [33]. Thus, metabolism can actively regulate the expression of specific genes.
suggest a novel model in which master transcription factors of effector CD4 T cells cooperate with epigenetic modifiers and metabolic sensors through physical interactions to direct specific gene expression.
Indeed, specific metabolic pathways are required for T cell activation, differentiation and function [34]. Potent induction of glucose and glutamine catabolism and dampening of lipid oxidation are crucial for effector T cell activation, a process dependent on the transcription factor c-Myc [35–37]. The importance of glucose metabolism to T lineage differentiation is further highlighted by the absence of a glucose transporter, Glut1, without which effector CD4 T cells fail to proliferate and differentiate [38]. Fatty acid synthesis also plays a preferential role in T cell differentiation. ACC1, the rate limiting enzyme for fatty acid synthesis, is shown to regulate Treg/Teff balance [39]. As well, HIF-1a, a regulator of glycolysis and oxidative phosphorylation, is another checkpoint regulator for Teff/Treg differentiation [40,41].
Another mechanism proposed for regulation of T cell lineage commitment by metabolism is through the generation of ligands for master transcription factors. Rorgt is an orphan nuclear receptor that was reported to require a cholesterol-based ligand for activation [47–49]. Recent work showed that the cholesterol synthesis and uptake programs are induced in Th17 cell differentiation and that inhibition of these pathways using chemical inhibitors limited Rorgt endogenous ligand and Th17 cell differentiation [50]. Santori et al. showed that critical enzymes of the cholesterol synthesis pathways, by providing endogenous ligand, are required for Rorgt function and Th17 cell differentiation [51]. Thus, specific metabolites can contribute to direct transcription of lineagespecific gene expression by collaborating with master transcription factors.
Intriguingly, commitment to the effector T cell lineages, Th1, Th2 and Th17, also exhibits a preference for particular metabolic pathways, although the mechanisms for such a requirement have only begun to be elucidated. Whereas the mTORC1 complex supports Th1 and Th17 differentiation, differentiation of Th2 cells require mTORC2 [42]. Amino acid deprivation, particularly cysteine and methionine, was reported to suppress Th17 but not Th1, Th2 or iTreg differentiation [43]. However, the loss of a specific amino acid transporter, Slc7a5, resulted in defective Th1 and Th17 effector T cell differentiation, suggesting an intricate mechanism for the requirement of amino acid metabolism that differs among effector T cell lineages [44]. Hypoxia supported better Th17 cell differentiation, a process dependent on HIF-1a [40]. Interestingly, the absence of HIF-1a only affected differentiation of Th17, but not Th1 or Th2 cells [40]. Finally, the cholesterol export and synthesis pathways, reciprocally regulated by LXR and sREBP [45], can regulate Th17 cell differentiation [46]. Thus, from nutrient transporters to metabolic sensors and enzymes, metabolism plays an active regulatory role in T cell lineage specificity. Several mechanisms have been proposed to explain the lineage specificity of metabolic regulation of effector CD4 T cells. Dang et al. elegantly showed that HIF1a, which preferentially regulates Th17 and Treg, but not Th1 or Th2 cells, form a tertiary complex with the master regulator Rorgt and the acetyltransferase p300. This complex, in turn, enhances the transcription of specific genes in the Th17 lineage. In contrast, HIF-1a can directly bind to Foxp3, but targets it for proteosomal degradation instead [40]. It is unclear how these interactions would in turn regulate genes in the metabolic pathways that are HIF-1a targets. These observations Current Opinion in Immunology 2015, 37:6–10
Conclusion CD4 T cell differentiation unfolds in the context of higher order regulatory networks initiated by epigenetic and metabolic modifications following T cell activation. These alterations define the landscape in which master transcription factors operate to guide the specificity of lineage program. Integration of additional environmental cues adds to the complexity of the transcriptional program, allowing for greater diversity within a lineage in response to the environment.
Acknowledgements This project was supported by the Evergrande Center for Immunologic diseases, Grants # NS030843, AI039671, NS076410, AI056299 and the Crohn’s and Colitis Foundation of America. C. Wang is supported by Multiple Sclerosis Society of Canada postdoctoral fellowship.
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39. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K et al.: De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 2014, 20:1327-1333. 40. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y et al.: Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011, 146:772-784. This paper describes a novel model where a master transcription factor can interact with a histone modifier and metabolic sensor to direct gene expression. 41. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR et al.: HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011, 208:1367-1376.
proliferation in the acquired immune response. Cell 2008, 134:97-111. 46. Cui G, Qin X, Wu L, Zhang Y, Sheng X, Yu Q et al.: Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 2011, 121:658-670. 47. Wang Y, Kumar N, Crumbley C, Griffin PR, Burris TP: A second class of nuclear receptors for oxysterols: regulation of RORalpha and RORgamma activity by 24Shydroxycholesterol (cerebrosterol). Biochim Biophys Acta 2010, 1801:917-923. 48. Wang Y, Kumar N, Solt LA, Richardson TI, Helvering LM, Crumbley C et al.: Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J Biol Chem 2010, 285:5013-5025.
42. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR et al.: The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 2011, 12:295-303.
49. Jin L, Martynowski D, Zheng S, Wada T, Xie W, Li Y: Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol Endocrinol 2010, 24:923-929.
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50. Hu X, Wang Y, Hao LY, Liu X, Lesch CA, Sanchez BM et al.: Sterol metabolism controls T(H)17 differentiation by generating endogenous RORgamma agonists. Nat Chem Biol 2015, 11:141-147. See annotation to Ref. [51].
44. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA: Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 2013, 14:500-508. 45. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA et al.: LXR signaling couples sterol metabolism to
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51. Santori FR, Huang P, van de Pavert SA, Douglass EF Jr, Leaver DJ, Haubrich BA et al.: Identification of natural RORgamma ligands that regulate the development of lymphoid cells. Cell Metab 2015, 21:286-297. The above two papers depict a model where metabolic changes can contribute to specific gene expression by providing ligands for master transcription factors.
www.sciencedirect.com
ScienceDirect Effector T cell differentiation: are master regulators of effector T cells still the masters? Chao Wang, Mary Collins and Vijay K Kuchroo Effector CD4 T cell lineages have been implicated as potent inducers of autoimmune diseases. Tbet, Gata3 and Rorgt are master transcriptional regulators of Th1, Th2 and Th17 lineages respectively and promote the distinct expression of signature cytokines. Significant progress has been made in understanding the transcriptional network that drives CD4 T cell differentiation, revealing novel points of regulation mediated by transcription factors, cell surface receptors, cytokines and chemokines. Epigenetic modifications and metabolic mediators define the transcriptional landscape in which master transcription factors operate and collaborate with a network of transcriptional modifiers to guide lineage specification, plasticity and function. Address Evergrande Center for Immunological Diseases, Harvard Medical School, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA Corresponding author: Kuchroo, Vijay K ([email protected])
Current Opinion in Immunology 2015, 37:6–10 This review comes from a themed issue on Autoimmunity Edited by Mark S Anderson and Fabienne Mackay
http://dx.doi.org/10.1016/j.coi.2015.08.001 0952-7915/Published by Elsevier Ltd.
The helper T cell paradigm introduced by Mosmann and Coffman has been extended to include the well characterized Th1, Th2 and Th17 cell subsets. Naive CD4 T cells acquire lineage specificity by engaging distinct sets of cytokines that activate JAK-STAT-proteins in the context of TCR signals, enabling lineage commitment by the expression of unique master transcription factors Tbet, Gata3 and Rorgt for Th1, Th2 and Th17 cells, respectively. While the importance of the master transcription factors is undisputable, they are clearly not sufficient to define the full extent of effector T cell differentiation and function. Recent studies reveal the complex regulatory network that orchestrates the lineage commitment process of Th17 cells [9,10] and Th2 cells [11]. Th17 cell differentiation is regulated by two opposing transcription network modules that co-exist and antagonize each other, which may, in part, enable the plasticity of the Th17 subset [10]. It is also clear that most transcription factors and other regulators operate only within a transcriptional landscape regulated by higher order epigenetic [12] and metabolic changes that in turn regulate effector CD4 T cell differentiation and function. So how important are master transcription factors in light of these relatively new discoveries affecting gene regulation in Teff cells? This review will focus on recent advances in our understanding of the influence of chromatin structure and cellular metabolism in effector T cell differentiation and function and how these changes can cooperate with master transcription factors and in turn regulate effector T cell lineage commitment.
Regulatory network Introduction Autoreactive T cells are present in both healthy people and in individuals suffering from autoimmune disease [1,2]. In animal models and humans, pathogenic autoreactive effector CD4 T cells (Teff) contribute to autoimmunity by producing cytokines, providing T cell help, provoking direct cellular injury and by recruiting other immune cells to inflammatory sites even in the presence of fully functional regulatory T cells [3–8]. Several lineages of Teff have been described, each with distinct signature cytokines that contribute to autoimmune diseases. Understanding the regulation of Teff lineage commitment and function, and the contribution of Teff to pathology is fundamental in defining novel approaches for the prevention and treatment of autoimmune diseases. Current Opinion in Immunology 2015, 37:6–10
The master regulators were defined as transcription factors that are both necessary and sufficient for the induction of signature cytokines for distinct effector CD4 T cell lineages. As more transcription factors are being discovered, the relative importance of master regulators was questioned [13,14]. For example, the defect in Th17 differentiation in Stat3 deficiency can only be partially rescued by Rorgt overexpression [13]. This is consistent with the finding that the induction of Rorgt is among the second-wave regulators and is necessarily preceded by the expression of pioneering factors such as Stat3, Batf and Irf4 [10]. The timing of Rorgt induction suggests the importance of higher order transcription factors in setting up the chromatin landscape for lineage-specific gene expression and/or for the induction of master regulators themselves. Indeed, cooperatively bound BATF and IRF4 were shown to contribute to initial chromatin accessibility in Th17 cells [9]. Some of these higher www.sciencedirect.com
Are master regulators of Teff cells still the masters? Wang, Collins and Kuchroo 7
order regulators, however, are not specific to a particular T cell lineage. A complete understanding of the T cell differentiation program will depend on appreciation of both the specific set of transcription factors and their hierarchical order, both of which are not yet fully elucidated. It should be appreciated that many transcription factors of the Th17 cell lineage are induced at the same time or after the expression of Rorgt [10]. Indeed, expression of Rorgt is not sufficient to define the transcriptional program for Th17 cells, as functional distinctions in Th17 responses have been defined in response to infection and in autoimmune settings [15,16]. It would be of great interest to decipher the interactions of these regulators with the master transcription factor and to understand how they can cooperatively regulate T cell lineage commitment, function and plasticity.
Epigenetic landscape and regulation of Teff differentiation Similar to the transcriptional network, the epigenetic landscape of effector T cell lineages is characterized in waves. Upon T cell activation, initial histone acetylation occurs in both Th1 and Th2 loci; lineage and locus specific patterns of histone modification only emerge subsequently [12]. Indeed, polarizing cytokines can regulate the epigenetic state of effector CD4 T cells and cause epigenetic changes that are reinforced in a STAT-dependent and master regulator-dependent process [17–19]. The master transcription factors are thought to specify the cytokine pathways that define lineages, however they may not be necessary for regulating the epigenetic status of all signature cytokines. In Th2 cells, Gata3 was shown to be required for DNA demethylation and hyperacetylation of the Il5 gene locus [20]. However, neither Il4 nor Il13 epigenetic marks are regulated by Gata3, suggesting the importance of other regulatory machinery [17,20]. In Th17 cells, histone modification of neither Il17a nor Il17f depends on RORgt and in fact epigenetic modification of very few genes requires RORgt as compared to pioneering transcription factors such as IRF4, BATF and STAT3 [9]. In addition to pioneering transcription factors such IRF4/ BATF for Th17 cells, the epigenetic landscape of effector T cell lineages can be regulated directly by components of histone modification machinery. Mta2, part of a histone deacetylase complex, is found to influence both Th1 and Th2 responses [21]. By performing genome-wide ChIPseq of the histone acyltransferase p300 in Th1, Th2 and Th17 cells, Vahedi et al. identified BACH2 as a crucial regulator of a large set of superenhancer elements shared among T cell lineages [22]. BACH2 deficiency, as compared to STAT, BATF or IRF4, resulted in the largest www.sciencedirect.com
loss of p300 binding to super-enhancer elements that regulate cell identity [22]. This is consistent with BACH2 being a broad suppressor of effector T cell differentiation in Th1, Th2 and Th17 cells [23]. Whereas master transcription factors may not be necessary for all epigenetic changes of signature genes, they can cooperate with epigenetic modifiers and allow selective regulation of gene expression. Indeed, in contrast to BACH2, some epigenetic modifiers can selectively regulate T cell lineages. Mina, a histone demethylase and as well as a ribosomal hydrolase, is identified as a novel positive regulator of Th17 cell differentiation [10]. Jmjd3 is a H3K27 demethylase and Jmjd3 deficiency is found to promote Th2 and Th17, but inhibit Th1 and iTreg cell differentiation [24]. Jmjd3 is also required for plasticity of effector T cells as Th2 or Th17 cells failed to be repolarized into Th1 cells. Interestingly, Jmjd3 is found to interact with Tbet but not Gata3, Foxp3 or Rorgt, providing a potential mechanism for its lineage specificity [24]. Thus epigenetic modifiers can couple with master transcription factors and drive effector T cell lineage commitment. Epigenetics plays a key role in the regulation of autoimmunity by modulating the accessibility of gene loci and transcriptional readiness [25]. Patients with autoimmune diseases were found to have abnormal DNA methylation and histone acetylation in cis-regulatory elements of signature cytokines in CD4 T cells [26–28]. Recent fine-mapping of genome-wide-association studies identified 90% of casual variants as non-coding and largely mapping to immune-cell enhancers [29]. In particular, in CD4 T cells, asthma-associated SNPs are enriched in Th2 cell enhancers [30]. SNPs highly associated with autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and type 1 diabetes, but not other non-autoimmune diseases, showed significantly higher overlap with super-enhancer elements [22]. It remains to be seen how epigenetic modifiers could collaborate with the network of transcription factors and contribute to T cell function.
Metabolic regulation of specific gene expression during Teff differentiation Activation and differentiation of T cells are accompanied by alterations in cellular metabolism. A key question is how these metabolic changes further influence the precise outcome of an immune response. Otto Warburg made the observation in 1958 that leukocytes in response to mitogen opt for a less energy-efficient aerobic glycolysis pathway as compared to oxidative phosphorylation [31], an observation later recapitulated in peripheral T cells [32], alluding to the importance of metabolism beyond the requirement for energy. It was not until 2013 that a specific mechanism was identified: Pearce et al. showed that glycolysis is required to promote T cell effector function by engaging/dis-engaging GAPDH, which Current Opinion in Immunology 2015, 37:6–10
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otherwise binds to the AU-rich element at the 30 end of IFNg and IL-2 mRNA and selectively inhibits their translation [33]. Thus, metabolism can actively regulate the expression of specific genes.
suggest a novel model in which master transcription factors of effector CD4 T cells cooperate with epigenetic modifiers and metabolic sensors through physical interactions to direct specific gene expression.
Indeed, specific metabolic pathways are required for T cell activation, differentiation and function [34]. Potent induction of glucose and glutamine catabolism and dampening of lipid oxidation are crucial for effector T cell activation, a process dependent on the transcription factor c-Myc [35–37]. The importance of glucose metabolism to T lineage differentiation is further highlighted by the absence of a glucose transporter, Glut1, without which effector CD4 T cells fail to proliferate and differentiate [38]. Fatty acid synthesis also plays a preferential role in T cell differentiation. ACC1, the rate limiting enzyme for fatty acid synthesis, is shown to regulate Treg/Teff balance [39]. As well, HIF-1a, a regulator of glycolysis and oxidative phosphorylation, is another checkpoint regulator for Teff/Treg differentiation [40,41].
Another mechanism proposed for regulation of T cell lineage commitment by metabolism is through the generation of ligands for master transcription factors. Rorgt is an orphan nuclear receptor that was reported to require a cholesterol-based ligand for activation [47–49]. Recent work showed that the cholesterol synthesis and uptake programs are induced in Th17 cell differentiation and that inhibition of these pathways using chemical inhibitors limited Rorgt endogenous ligand and Th17 cell differentiation [50]. Santori et al. showed that critical enzymes of the cholesterol synthesis pathways, by providing endogenous ligand, are required for Rorgt function and Th17 cell differentiation [51]. Thus, specific metabolites can contribute to direct transcription of lineagespecific gene expression by collaborating with master transcription factors.
Intriguingly, commitment to the effector T cell lineages, Th1, Th2 and Th17, also exhibits a preference for particular metabolic pathways, although the mechanisms for such a requirement have only begun to be elucidated. Whereas the mTORC1 complex supports Th1 and Th17 differentiation, differentiation of Th2 cells require mTORC2 [42]. Amino acid deprivation, particularly cysteine and methionine, was reported to suppress Th17 but not Th1, Th2 or iTreg differentiation [43]. However, the loss of a specific amino acid transporter, Slc7a5, resulted in defective Th1 and Th17 effector T cell differentiation, suggesting an intricate mechanism for the requirement of amino acid metabolism that differs among effector T cell lineages [44]. Hypoxia supported better Th17 cell differentiation, a process dependent on HIF-1a [40]. Interestingly, the absence of HIF-1a only affected differentiation of Th17, but not Th1 or Th2 cells [40]. Finally, the cholesterol export and synthesis pathways, reciprocally regulated by LXR and sREBP [45], can regulate Th17 cell differentiation [46]. Thus, from nutrient transporters to metabolic sensors and enzymes, metabolism plays an active regulatory role in T cell lineage specificity. Several mechanisms have been proposed to explain the lineage specificity of metabolic regulation of effector CD4 T cells. Dang et al. elegantly showed that HIF1a, which preferentially regulates Th17 and Treg, but not Th1 or Th2 cells, form a tertiary complex with the master regulator Rorgt and the acetyltransferase p300. This complex, in turn, enhances the transcription of specific genes in the Th17 lineage. In contrast, HIF-1a can directly bind to Foxp3, but targets it for proteosomal degradation instead [40]. It is unclear how these interactions would in turn regulate genes in the metabolic pathways that are HIF-1a targets. These observations Current Opinion in Immunology 2015, 37:6–10
Conclusion CD4 T cell differentiation unfolds in the context of higher order regulatory networks initiated by epigenetic and metabolic modifications following T cell activation. These alterations define the landscape in which master transcription factors operate to guide the specificity of lineage program. Integration of additional environmental cues adds to the complexity of the transcriptional program, allowing for greater diversity within a lineage in response to the environment.
Acknowledgements This project was supported by the Evergrande Center for Immunologic diseases, Grants # NS030843, AI039671, NS076410, AI056299 and the Crohn’s and Colitis Foundation of America. C. Wang is supported by Multiple Sclerosis Society of Canada postdoctoral fellowship.
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