Regulatory T Cells: the Many Faces of Foxp3

Georgiev, Peter; Charbonnier, Louis-Marie; Chatila, Talal

doi:10.1007/s10875-019-00684-7

Cited by 167 publications

(156 citation statements)

References 164 publications

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“…In allergic asthma, iTregs are generated de novo by specialized lung tissue–resident macrophages through secretion of TGF-β and retinal dehydrogenases ( 14 ). TGF-β is important in the generation of antigen-specific FoxP3 + Tregs, and its abrogation in vivo leads to uncontrolled Th2 allergic asthma ( 15 ). Although iTregs may play a major role in generation of tolerance to airborne allergens, additional tolerance mechanisms exist, including diversion of allergen-specific cells to non-Th2 cells, peripheral deletion of autoreactive cells to harmless allergens, and allergen ignorance ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

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IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33

Khumalo¹,

Kirstein²,

Hadebe³

et al. 2020

JCI Insight

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Impaired tolerance to innocuous particles during allergic asthma has been linked to increased plasticity of FoxP3 + regulatory T cells (Tregs) reprogramming into pathogenic effector cells, thus exacerbating airway disease. However, failure of tolerance mechanisms is driven by Th2 inflammatory signals. Therefore, the in vivo role of canonical IL-4 receptor α (IL-4Rα) signaling, an essential driver of Th2-type airway responses to allergens, on the regulatory function of FoxP3 + Tregs in allergic asthma was explored. Here, we used transgenic Foxp3 cre IL-4Rα –/lox and littermate control mice to investigate the role of IL-4 and IL-13 signaling via Tregs in house dust mite–induced (HDM-induced) allergic airway disease. We sensitized mice intratracheally on day 0, challenged them on days 6–10, and analyzed airway hyperresponsiveness (AHR), airway inflammation, mucus production, and cellular profile on day 14. In the absence of IL-4Rα responsiveness on FoxP3 + Tregs, exacerbated AHR and airway inflammation were shown in HDM-sensitized mice. Interestingly, reduced induction of FoxP3 + Tregs accompanied increased IL-33 alarmin production and type 2 innate lymphoid cell activation in the lung, exacerbating airway hyperreactivity and lung eosinophilia. Taken together, our findings indicate that IL-4Rα–unresponsive FoxP3 + Tregs result in exaggerated innate Th2-type, IL-33–dependent airway inflammation and a break in tolerance during allergic asthma.

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Section: Introductionmentioning

confidence: 99%

“…Th2 cells can impair induction of Tregs either by hijacking them to become effector Th2 cells or by limiting their ability to act as active Th2 suppressor cells ( 15 ). These mechanisms include reprogramming of Tregs toward a pathogenic effector T cell phenotype leading to unrestrained Th2 airway inflammatory response ( 18 – 22 ).…”

Section: Introductionmentioning

confidence: 99%

IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33

Khumalo¹,

Kirstein²,

Hadebe³

et al. 2020

JCI Insight

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“…[24] Loss-of-function mutations of the FOXP3 gene can conduce to the functional de ciency of Treg cells in animal and human models , [25] which can further inhibit natural killer cells, macrophages, and dendritic cells to affecting the maternal immune tolerance. [26] SNP rs2232365 located in a putative binding site for the transcription factor GATA-3 and its polymorphism was likely to contribute to variant(s) in the quantity or quality of FOXP3.…”

Section: Discussionmentioning

confidence: 99%

Novel Association Between FOXO3 rs2232365 Polymorphism and Late-Onset Preeclampsia: A Case-Control Candidate Genetic Study

Pan

Wei

Wang

et al. 2020

Preprint

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BackgroundBoth genetic susceptibility and dysregulated lipid metabolism are important susceptibilities to preeclampsia. In the study, we devote to investigate the associations of FOXO3 and TLR7 genetic polymorphisms with preeclampsia in a Chinese population.MethodsThis case-control study involved 335 Han Chinese pregnant women, including 177 pregnant women with preeclampsia and 158 healthy controls. The preeclampsia group was further sub-grouped into early-onset preeclampsia (EOPE, n=70）and late-onset preeclampsia (LOPE, n=107）. Three single nucleotide polymorphisms SNPs , including FOXO3 rs2232365, rs3761548, and TLR7 rs3853839 were genotyped by multiplex PCR for targeted next-generation sequencing. The χ2 test and multiple interaction effect analyses were performed to determine the association of three SNPs with serum lipid levels and thyroid function in women with preeclampsia.ResultsOur study showed that SNP rs2232365 C allele frequencies were significantly associated with the occurrence of LOPE (P=0.022, odds ratio = 1.72 (0.95 CI: 1.23-2.41)). The genotype (CC vs TT+CT) distribution of rs2232365 revealed a significant association with LOPE (P=0.004, odds ratio = 3.497 (0.95 CI: 1.498-8.164)). No significant difference was found in the genotype and allele frequencies of rs3761548 and rs3853839 between controls and cases (P>0.05). Moreover, the genotype CC of rs2232365 was significantly correlated with increased TG/HDL levels in the LOPE group (all p=0.014). ConclusionsThe polymorphisms of rs2232365 are associated with the risk of LOPE and may modulate TG/HDL levels in pregnant women with LOPE.

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“…Increasing evidence emphasizes the role of T cells as important drivers and modulators of atherogenesis [ 1 , 2 ]. Regulatory T cells (Tregs) are capable of suppressing exacerbated inflammatory responses to enforce immunological tolerance and homeostasis [ 3 , 4 ]. This specialized subset of CD4 + T cells is phenotypically characterized by constitutively high expression of the interleukin (IL)-2 receptor α chain (CD25) on their surfaces.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T Cell Metabolism in Atherosclerosis

Baardman

Lutgens

2020

Metabolites

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Regulatory T cells (Tregs) are capable of suppressing excessive immune responses to prevent autoimmunity and chronic inflammation. Decreased numbers of Tregs and impaired suppressive function are associated with the progression of atherosclerosis, a chronic inflammatory disease of the arterial wall and the leading cause of cardiovascular disease. Therefore, therapeutic strategies to improve Treg number or function could be beneficial to preventing atherosclerotic disease development. A growing body of evidence shows that intracellular metabolism of Tregs is a key regulator of their proliferation, suppressive function, and stability. Here we evaluate the role of Tregs in atherosclerosis, their metabolic regulation, and the links between their metabolism and atherosclerosis.

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Regulatory T Cells: the Many Faces of Foxp3

Cited by 167 publications

References 164 publications

IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33

IL-4Rα signaling in CD4+CD25+FoxP3+ T regulatory cells restrains airway inflammation via limiting local tissue IL-33

Novel Association Between FOXO3 rs2232365 Polymorphism and Late-Onset Preeclampsia: A Case-Control Candidate Genetic Study

Regulatory T Cell Metabolism in Atherosclerosis

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