Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function

Field, Cameron S.; Baixauli, Francesc; Kyle, Ryan; Puleston, Daniel J.; Cameron, Alanna M.; Sanin, David E.; Hippen, Keli L.; Loschi, Michaël; Thangavelu, Govindarajan; Corrado, Mauro; Edwards-Hicks, Joy; Grzes, Katarzyna M.; Pearce, Edward J.; Blazar, Bruce R.; Pearce, Erika L.

doi:10.1016/j.cmet.2019.11.021

Cited by 272 publications

(219 citation statements)

References 88 publications

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“…ACAA2 catalyzes steps in FAO ( 74 ) and there were multiple genes upregulated ( NDUFA4, NDUFAF4, NDUFB11 , and NDUFS5 ) that correspond to accessory subunits of mitochondrial complex I ( 75, 76 ). Importantly, SIRT4, which regulates FAO via inhibition of PPARA transcription ( 77 ) and FABP5, which is a known intracellular lipid chaperone ( 78, 79 ) were upregulated as well. Furthermore, enrichment of CD69 and costimulatory factor CD9 would suggest arachidonic acid treated T regs are more activated ( 80–82 ).…”

Section: Resultsmentioning

confidence: 99%

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: 99%

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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“…Furthermore, aKG directly augmenting OXPHOS. However, the association of OXPHOS to Treg function is complex; inhibition of OXPHOS can suppresses Treg suppressive functions (Beier et al, 2015;Weinberg et al, 2019), but decreased mitochondrial integrity, due to loss of the fatty acid binding protein FABP5, has been found to enhance Treg function (Field et al, 2019). Here, we identified mitochondrial complex II as a critical negative regulator of Treg differentiation: abrogation of complex II by either malonate or 3-NP restored Treg polarization in the presence of aKG and decreased the production of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly though, mitochondrial metabolism plays a role in the function of both Treg and Th1 cells--mitochondrial integrity as well as complex III activity of the electron transport chain (ETC) are required for Treg suppressive activity (Beier et al, 2015;Field et al, 2019;Miska et al, 2019;Weinberg et al, 2019) whereas complex II activity is a requirement for terminal Th1 function (Bailis et al, 2019). Consistent with a role for OXPHOS in Th1 activity, the catalytic conversion of glutamine to alpha-ketoglutarate (αKG), which directly fuels the tricarboxylic acid cycle (TCA), has been shown to play a critical role in Th1 cell differentiation (Johnson et al, 2018), with αKG directly rescuing Th1 differentiation under glutamine-deprived conditions (Klysz et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

αKG inhibits Regulatory T cell differentiation by coupling lipidome remodelling to mitochondrial metabolism

Matias

Yong

Foroushani

et al. 2020

Preprint

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The differentiation of CD4 T cells to a specific effector fate is metabolically regulated, integrating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) with transcriptional and epigenetic changes. OXPHOS is tightly coordinated with the tricarboxylic acid (TCA) cycle but the precise role of TCA intermediates in CD4 T cell differentiation remain unclear. Here we demonstrate that α-ketoglutarate (α-KG) inhibited regulatory T cell (Treg) generation while conversely, increasing Th1 polarization. In accord with these data, α-KG promoted the effector profile of Treg-polarized chimeric antigen receptor-engineered T cells against the ErbB2 tumor antigen. Mechanistically, α-KG significantly altered transcripts of genes involved in lipid-related processes, inducing a robust lipidome-wide remodelling and decreased membrane fluidity. A massive increase in storage and mitochondria lipids was associated with expression of mitochondrial genes and a significantly augmented OXPHOS. Notably, inhibition of succinate dehydrogenase activity, the bridge between the TCA cycle and the electron transport chain, enforced Treg generation. Thus, our study identifies novel connections between α-KG, lipidome remodelling and OXPHOS in CD4 T cell fate decisions.

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“…Several studies have indicated that FAO is critically needed to support Treg function [15,55,65,66]. Carnitine palmitoyl transferase‐1 (CPT1) enzyme is essential for FAO.…”

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

“…indicated that etomoxir inhibits different targets beside CPT1a [67,68]. However, it should be noted that Tregs can use CPT1a‐independent pathways to utilize fatty acids and that the translocation of short‐ or medium‐chain FAs does not involve CPT1a [66].…”

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

2020

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Regulatory T cells (Tregs) are critical for peripheral immune tolerance and homeostasis, and altered Treg behavior is involved in many pathologies, including autoimmunity and cancer. The expression of the transcription factor FoxP3 in Tregs is fundamental to maintaining their stability and immunosuppressive function. Recent studies have highlighted the crucial role that metabolic reprogramming plays in controlling Treg plasticity, stability, and function. In this review, we summarize how the availability and use of various nutrients and metabolites influence Treg metabolic pathways and activity. We also discuss how Treg‐intrinsic metabolic programs define and shape their differentiation, FoxP3 expression, and suppressive capacity. Lastly, we explore how manipulating the regulation of Treg metabolism might be exploited in different disease settings to achieve novel immunotherapies.

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Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function

Cited by 272 publications

References 88 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

αKG inhibits Regulatory T cell differentiation by coupling lipidome remodelling to mitochondrial metabolism

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

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