Differential Regulation of Human Treg and Th17 Cells by Fatty Acid Synthesis and Glycolysis

Cluxton, Deborah; Petrasca, Andreea; Moran, Barry; Fletcher, Jean M.

doi:10.3389/fimmu.2019.00115

Cited by 158 publications

(142 citation statements)

References 39 publications

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“…Previous reports have found human T regs to be engaged in both FAO and glycolysis to support their expansion ( 52, 56 ). To examine whether LCFAs are specifically upregulating FAO and not simply increasing activation status of cells, we measured glycolysis activity via extracellular acidification rate by Seahorse analysis.…”

Section: Resultsmentioning

confidence: 93%

“…However, recent reports revealed different metabolic requirements of T regs during development versus those needed in established T regs for proper function. In human T regs , OXPHOS and glycolytic engagement upon activation have been reported ( 52, 56 ), and it is known that glycolysis must be engaged to prevent enolase-1 suppression of FoxP3 ( 114 ). However, T regs have lower measured ECAR relative to other Th-effector subsets ( 115 ), and CD45RO + T regs have greater mitochondrial mass relative to CD45RO + T eff cells ( 56 ).…”

Section: Discussionmentioning

confidence: 99%

“…In human T regs , OXPHOS and glycolytic engagement upon activation have been reported ( 52, 56 ), and it is known that glycolysis must be engaged to prevent enolase-1 suppression of FoxP3 ( 114 ). However, T regs have lower measured ECAR relative to other Th-effector subsets ( 115 ), and CD45RO + T regs have greater mitochondrial mass relative to CD45RO + T eff cells ( 56 ). It can be considered that glycolytic restriction or FAO engagement favors T reg development, then once the T reg program is established glycolysis is re-engaged in order to preserve the phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

Pompura

Wagner

Kitz

et al. 2020

Preprint

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25FoxP3 positive regulatory T cells (T regs ) rely on fatty acid b-oxidation (FAO)-driven OXPHOS for 26 differentiation and function. Recent data have demonstrated a role for T regs in the maintenance of 27 tissue homeostasis with tissue-resident T regs possessing tissue-specific transcriptomes. However, 28 specific signals that establish these tissue-resident T regs programs are largely unknown. As T regs 29 metabolically rely on FAO, and considering the lipid-rich environments of tissues, we 30 hypothesized that environmental lipids drive T reg homeostasis. Using human adipose tissue as a 31 model for tissue residency, we identify oleic acid as the most prevalent free fatty acid in human 32 adipose tissue. Mechanistically, oleic acid amplifies T reg FAO-driven OXPHOS metabolism, 33 creating a positive feedback mechanism that induces the expression of Foxp3 and enhances 34 phosphorylation of STAT5, which acts to stabilize the T reg lineage and increase suppressive 35 function. Comparing the transcriptomic program induced by oleic acid to that of the pro-36 inflammatory arachidonic acid, we find that T regs sorted from peripheral blood and adipose of 37 healthy donors transcriptomically resemble the oleic acid in vitro treated T regs , whereas T regs 38 obtained from the adipose tissue of relapsing-remitting MS patients more closely resemble an 39 arachidonic acid profile. Finally, we find that oleic acid concentrations are reduced in the fat tissue 40 of MS patients, and exposure of dysfunctional MS T regs to oleic acid restores defects in their 41 suppressive function. These data demonstrate the importance of fatty acids in regulating tissue 42 inflammatory signals. 43 44 45 Metabolic signatures of T cells are intricately linked to their differentiation and activation 46 status. Metabolic pathways facilitate cellular functions, therefore linking metabolic remodeling to 47 the development, activation, differentiation, and survival of T cells. Upon activation, quiescent, 48 naïve T cells become rapidly dividing effector T (T eff ) cells and switch their metabolic program 49 from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, known as the Warburg effect, in 50order to meet the increase in demand for cellular energy and biomass (1, 2). However, despite 51 having similar developmental origins, regulatory T cells (T regs ) rely predominantly on a fatty acid 52 b-oxidation (FAO)-driven OXPHOS metabolic program to maintain their suppressive phenotype, 53 which is further promoted by the expression of FoxP3 (3-5). Forced expression of FoxP3 in T cells 54 suppresses glycolysis-related genes while inducing lipid and oxidative metabolic-related genes 55 that are required for maximum suppression (4). In addition, cytokines that promote T reg 56 differentiation, such as TGF-b (6), activate AMPK (7) and promote FAO to skew naïve T cells into 57 a T reg phenotype (3, 8). Furthermore, T reg differentiation and suppression are reduced by inhibiting 58 FAO (3), highlighting the importance of FAO-driven OXPHOS in the in...

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

Pompura

Wagner

Kitz

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…A growing body of evidence suggests that Treg homeostasis relies on the ability to oxidize fatty acids. Tregs oxidize exogenous free fatty acids (palmitate), and the blockage of glycolysis, lack of exogenous glucose, or excess palmitate in the media will result in Treg enrichment, suppressive activity, and differentiation from CD4 + precursors[21, 22,42,43]. In addition, ex vivo Tregs will take up exogenous FFAs at a greater rate when they are rapidly proliferating, and during activation [37,44].…”

Section: Discussionmentioning

confidence: 99%

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

Rodia

Tambini

et al. 2019

Preprint

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Objective: Cellular metabolism is a key regulator of CD4 + Foxp3 + regulatory T cell (Treg) homeostasis, but the foundational studies in this area use free fatty acid treatment as a proxy for plasma triglycerides. In vivo, plasma triglyceride is the main source of fatty acids for cells, not free fatty acids. Design/Results: Using apolipoprotein C-III transgenic and LDLr -/mice, we report that the loss of lipoprotein triglycerides transport in these models results in protection from DSS-colitis and accumulation of intestinal Tregs and plasma IL-10. Total loss of apoC-III increases colitis severity. Tregs exposed to apoC-III increase lipolysis and fatty acid oxidation and apoC-III inhibits Bodipytriglyceride uptake. Therapeutic treatment of WT mice with apoC-III-containing lipoproteins protects mice from colitis. Conclusion: Our data suggest that therapies that reduce apoC-III could have negative effects in patients who are at risk of IBD, and conversely, that apoC-III could be a new therapeutic target to stimulate intestinal Tregs and IL-10 for the management of IBD. These data identify apoC-III and lipoprotein metabolism as a novel regulator of tolerance in the intestine. Summary Box * What is already known about this subject:§ The relative capacity to use either glucose or FFA to generate acetyl CoA for mitochondrial fatty acid oxidation is a critical driver of Treg and T cell activity and proliferation. § ApoC-III is a known regulator of triglyceride and fatty acid metabolism in cells via LPL and LDLr endocytosis pathways § ApoC-III is reduced in Crohn's and Colitis patients. * What are the new findings:§ We show that Tregs express triglyceride transporters, and that LDLr expression is enriched in Tregs from the mesenteric lymph nodes. § We show that T cells are capable of endocytosing triglyceride from lipoproteins, and this process is inhibited by apoC-III. § Tregs from apoC-III Tg are metabolically unique from WT Tregs and they upregulate the genes of lipolysis, and have an increase in basal respiration. § The inhibition of TAG endocytosis, using 2 different models (LDLr KO and apoC-IIItransgenic mice), protects mice from colitis and stimulates the accumulation of Tregs and IL-10 in the gut. § Intraperitoneal delivery of apoC-III on chylomicrons protects WT mice from DSS colitis. * How might it impact on clinical practice in the foreseeable future?§ Due to the protective role apoC-III plays in these mouse models of colitis, IBD risk should be carefully considered before prescribing patient anti-apoC-III lipid-lowering therapies.the TAG for fuel through two processes: the hydrolysis of TAG to free fatty acids (FFA) via membrane-bound lipoprotein lipase (LPL) and the subsequent transport of those FFAs into the cell, or alternatively, endocytosis of lipoprotein TAG via the low-density lipoprotein receptor (LDLr), and the subsequent intracellular hydrolysis, oxidation, or storage of those FFAs. The way that a cell encounters a lipid fuel (either as a FFA bound to albumin or as a holoparticle lipoprotein) as sign...

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“…However, Treg proliferation demands additional energy provided by enhanced glycolysis [ 10 ]. Recent studies confirm that the glycolytic pathway is necessary for Treg activation as human Treg cultured ex vivo in the presence of the anti-CD3 antibody, irradiated antigen-presenting cells, and IL-2, showed elevated glycolysis in comparison to the conventional T cells [ 11 ]. In addition, when cultured in vitro, Treg engage both glycolysis and FAO in contrast to the conventional T cells that utilize only glycolysis [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Ethyl Pyruvate Promotes Proliferation of Regulatory T Cells by Increasing Glycolysis

et al. 2020

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Ethyl pyruvate (EP), a stable form of pyruvate, has shown beneficial effects in animal models of shock, ischemia/reperfusion injury, and sepsis due to its potent anti-oxidant and anti-inflammatory properties. Our recent study demonstrated that EP application prevented the clinical manifestation of type 1 diabetes in mice by augmenting regulatory T cell (Treg) number and function. Our present study shows that EP increases Treg proliferation and suppressive function (perforin and IL-10 expression) during in vitro differentiation from conventional CD4+CD25− T cells. Enhanced expansion of Treg after EP treatment correlated with increased ATP levels and relied on increased glycolysis. Inhibition of oxidative phosphorylation did not attenuate EP stimulatory effects, suggesting that this metabolic pathway was not mandatory for EP-driven Treg proliferation. Moreover, EP lowered the expression of carnitine palmitoyltransferase I, an enzyme involved in fatty acid oxidation. Further, the stimulatory effect of EP on Treg proliferation was not mediated through inhibition of the mTOR signaling pathway. When given in vivo either intraperitoneally or orally to healthy C57BL/6 mice, EP increased the number of Treg within the peritoneal cavity or gut-associated lymphoid tissue, respectively. In conclusion, EP promotes in vitro Treg proliferation through increased glycolysis and enhances Treg proliferation when administered in vivo.

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Differential Regulation of Human Treg and Th17 Cells by Fatty Acid Synthesis and Glycolysis

Cited by 158 publications

References 39 publications

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

Oleic acid Induces Tissue Resident FoxP3 Regulatory T cell Lineage Stability and Suppressive Functions

ApoC-III overexpression and LDLr-/- protect mice from DSS-colitis: identifying a new role for lipoprotein metabolism in Tregs

Ethyl Pyruvate Promotes Proliferation of Regulatory T Cells by Increasing Glycolysis

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