Mitochondrial and cytosolic roles of <scp>PINK</scp>1 shape induced regulatory T‐cell development and function

Ellis, Gavin I.; Li, Zhi; Akundi, Ravi Shankar; Martí, Francesc

doi:10.1002/eji.201343571

Cited by 33 publications

(41 citation statements)

References 36 publications

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“…Thus, the observed increases in OCR could be attributed to increases in total numbers of mitochondria rather than individual mitochondria increasing their respiratory rates. Basal respiration was found to be greater than or equal to maximal respiration rates (Figure 1B-C and Supplemental Figure 3A) in most donors, which is consistent with previous reports in human and murine T regs ( 48, 52–54 ). We also observed a decrease in the overall spare respiratory capacity in the presence of oleic acid (Supplemental Figure 3B).…”

Section: Resultssupporting

confidence: 92%

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: Resultssupporting

confidence: 92%

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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“…We demonstrated in early studies that primary human naïve CD4 + T‐cells differentiate into suppressor Tregs in the presence of TGF‐ß and IL‐2 only after undergoing multiple rounds of cell division . In light of our results, we questioned whether the antiproliferative action of rapamycin and dual inhibitors was compatible with the IL‐2‐dependent differentiation of naïve T‐cells into iTregs.…”

Section: Resultsmentioning

confidence: 85%

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

et al. 2017

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The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI-103 and PKI-587 inhibitors interfered IL-2-dependent responses in T-cells. However, in contrast to the inhibitory effects in non-Treg T-cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI-103, and PKI-587 targeted different signaling events and induced different metabolic patterns in primary T-cells. Similar to rapamycin, in vivo administration of PI-103 and PKI-587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T-cells and support their potential as a novel therapeutic option in transplantation.

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“…In fact FOXO3a, is the only confirmed transcription factor shown to regulate PINK1 to date, with several FOXO binding elements (FBEs) identified in the PINK1 promoter. As PINK1 is also important for maximal PI3-kinase/Akt signalling [41,96,108], it is thought that PINK1 may be transcribed so that the system is "ready" to be maximally responsive to a returned stimulus, thereby having potential to confer short term protection [35] and stress resistance.…”

Section: Pten and Foxo Induction Of Pink1 In Cancer Cellsmentioning

confidence: 99%

PINK1 signalling in cancer biology

O’Flanagan¹,

O’Neill²

2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Mitochondrial and cytosolic roles of PINK1 shape induced regulatory T‐cell development and function

Cited by 33 publications

References 36 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

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

PINK1 signalling in cancer biology

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