Differential effect of DJ-1/PARK7 on development of natural and induced regulatory T cells

Singh, Yogesh; Chen, Hong; Zhou, Yuetao; Föller, Michael; Mak, Tak W.; Salker, Madhuri S.; Läng, Florian

doi:10.1038/srep17723

Cited by 34 publications

(43 citation statements)

References 56 publications

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“…2A, C). As previously described, activated levels of AKT/Rictor was shown to attenuate the development of Tregs [11,34,35]. As illustrated in Figure 2D, we showed that iTreg from ASM -/-mice have a reduction in Rictor, mTOR and AKT (serine 473) phosphorylation protein levels when compared to iTreg from ASM +/+ mice.…”

Section: Foxp3mentioning

confidence: 51%

“…Recently, Treg has been described as being neuroprotective, by modulating oxidative stress and inflammation in microglial cells, thereby ameliorating neurodegeneration in Parkinson´s disease [10,11]. The development, maintenance, and effector function of Treg is dependent on the cardinal transcription factor Foxp3 [12][13][14][15][16][17].…”

Section: Foxp3mentioning

confidence: 99%

“…To differentiate naïve T cells into iTreg, plates were pre-treated with a ratio of 1:2:anti-CD3:anti-CD28 (1.0 µg/ml anti-CD3: 2.0 µg/ml anti-CD28) [11]. CD4 +…”

Section: Itreg Differentiationmentioning

confidence: 99%

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Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development

Zhou

Salker

Walker

et al. 2016

Cell Physiol Biochem

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Background/Aims: Regulatory T cell (Treg) is required for the maintenance of tolerance to various tissue antigens and to protect the host from autoimmune disorders. However, Treg may, indirectly, support cancer progression and bacterial infections. Therefore, a balance of Treg function is pivotal for adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme involved in the production of ceramide by breaking down sphingomyelin. Previous studies in T-cells have suggested that ASM is involved in CD28 signalling, T lymphocyte granule secretion, degranulation, and vesicle shedding similar to the formation of phosphatidylserine-exposing microparticles from glial cells. However, whether ASM affects the development of Treg has not yet been described. Methods: Splenocytes, isolated Naive T lymphocytes and cultured T cells were characterized for various immune T cell markers by flow cytometery. Cell proliferation was measured by Carboxyfluorescein succinimidyl ester (CFSE) dye, cell cycle analysis by Propidium Iodide (PI), mRNA transcripts by q-RT PCR and protein expression by Western Blotting respectively. Results: ASM deficient mice have higher number of Treg compared with littermate control mice. In vitro induction of ASM deficient T cells in the presence of TGF-β and IL-2 lead to a significantly higher number of Foxp3⁺ induced Treg (iTreg) compared with control T-cells. Further, ASM deficient iTreg has less AKT (serine 473) phosphorylation and Rictor levels compared with control iTreg. Ceramide C6 led to significant reduction of iTreg in both ASM deficient and WT mice. The reduction in iTreg leads to induction of IL-1β, IL-6 and IL-17 but not IFN-γ mRNA levels. Conclusion: ASM is a negative regulator of natural and iTreg.

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Section: Foxp3mentioning

confidence: 51%

Section: Foxp3mentioning

confidence: 99%

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Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development

Zhou

Salker

Walker

et al. 2016

Cell Physiol Biochem

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“…Naive T Cells Isolation-To perform the Th differentiation or iTreg induction experiments, naive CD4 ϩ CD62L highϩ CD25 Ϫ T cells were isolated using magnetic bead selection from spleen and lymph nodes as described earlier (68,69). To isolate the CD4 ϩ T cells, the spleen and lymph nodes (inguinal, axillary, brachial, mediastinal, superficial cervical, mesenteric) were collected from the mice and macerated using a syringe plunger.…”

Section: Methodsmentioning

confidence: 99%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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CD4؉ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumors and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na ؉ /H ؉ exchanger 1 (NHE1; gene name Slc9␣1)) is critically important for regulating intracellular pH (pH i ), cell volume, migration, and cell survival. The pH i influences cytokine secretion, activities of membrane-associated enzymes, ion transport, and other effector signaling molecules such as ATP and Ca 2؉ levels. However, whether NHE1 regulates Th9 cell development or IL-9 secretion has not yet been defined. The present study explored the role of NHE1 in Th9 cell development and function. Th cell subsets were characterized by flow cytometry and pH i was measured using 2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester (BCECF-AM) dye. NHE1 functional activity was estimated from the rate of realkalinization following an ammonium pulse. Surprisingly, in Th9 cells pH i and NHE1 activity were significantly higher than in all other Th cell subsets (Th1/Th2/Th17 and induced regulatory T cells (iTregs)). NHE1 transcript levels and protein abundance were significantly higher in Th9 cells than in other Th cell subsets. Inhibition of NHE1 by siRNA-NHE1 or with cariporide in Th9 cells down-regulated IL-9 and ATP production. NHE1 activity, Th9 cell development, and IL-9 production were further blunted by pharmacological inhibition of protein kinase Akt1/Akt2. Our findings reveal that Akt1/Akt2 control of NHE1 could be an important physiological regulator of Th9 cell differentiation, IL-9 secretion, and ATP production. CD4ϩ T cells participate in the regulation of the immune response during infections, autoimmunity, and cancer. CD4 ϩ T cells are an important and essential arm of the adaptive immune system (1). CD4 ϩ T cells can be divided into various subtypes based upon their cytokine secretion: T helper 1 (Th1) 4 cells produce IFN-␥ (1, 2), Th2 cells produce IL-4, IL-5, and IL-13 (3), Th17 cells produce IL-17 (4 -6), Th9 cells produce IL-9 (7-9), and suppressive regulatory T cells (Tregs) produce TGF-␤ and IL-10 (10). A great deal of experimental effort has been dedicated to decipher the development and function of various Th cell subsets. However, Th9 cell development and function remain incompletely understood.Th9 cells are a recently characterized Th cell subset recognized by their potent production of IL-9. Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11, 12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7, 13-23). The development and function of Th9 cells are regulated ...

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“…After transcriptional induction and translational modifications, SGK1 is activated rapidly by highly elaborate post‐translational modifications, particularly reversible protein phosphorylation (5). This intracellular phosphorylation is accomplished by PI3K (6), 3‐phosphoinositide‐dependent kinase 1 (7), and mammalian target of rapamycin complexes 1 (8) and 2 (9). PI3K‐dependent activation of SGK1 is elicited by insulin (10), growth factors (11), IGF‐1 (12), estrogen (13), androgen (14), angiotensin II (15), follicle‐stimulating hormone, thrombin, and corticosterone (16).…”

mentioning

confidence: 99%

Involvement of serum glucocorticoid‐regulated kinase 1 in reproductive success

Lou

Mao

et al. 2016

FASEB j.

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Reproductive processes, in particular events that concern pregnancy, are fine-tuned to produce offspring. Reproductive success is of prime importance for the survival of every species. The highly conserved and ubiquitously expressed serum glucocorticoid-regulated kinase 1 (SGK1) was first implicated in infertility as a regulator of a Na channel. In this review, we emphasize the prominent role of SGK1 during early pregnancy: 1) balancing uterine luminal fluid secretion and reabsorption to aid blastocyst adhesion and to import nutrients and energy; 2) transducing signals from the blastocyst to the receptive endometrium; 3) inducing multiple genes that are involved in uterine receptivity and trophoblast invasion; 4) regulating cell differentiation and antioxidant defenses at the fetomaternal interface; and 5) contributing to the proliferation and survival of decidual stromal cells. Accordingly, SGK1 coordinates many cellular processes that are crucial to reproductive activities. Aberrant expression or function of SGK1 results in implantation failure and early pregnancy loss. Further investigation of the molecular mechanisms of the function of SGK1 might provide novel diagnostic tools and interventions for reproductive complications.-Lou, Y., Hu, M., Mao, L., Zheng, Y., Jin, F. Involvement of serum glucocorticoid-regulated kinase 1 in reproductive success.

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Differential effect of DJ-1/PARK7 on development of natural and induced regulatory T cells

Cited by 34 publications

References 56 publications

Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development

Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Involvement of serum glucocorticoid‐regulated kinase 1 in reproductive success

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