Foxp3+ Tregs are recruited to the retina to repair pathological angiogenesis

Deliyanti, Devy; Talia, Dean; Zhu, Tong; Maxwell, Mhairi J; Agrotis, Alex; Jerome, Jack R; Hargreaves, Emily M; Gerondakis, Steven Demetrious; Hibbs, Margaret L.; Mackay, Fabienne; Wilkinson-Berka, Jennifer L.

doi:10.1038/s41467-017-00751-w

Cited by 75 publications

(71 citation statements)

References 55 publications

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“…Further, we have previously demonstrated that CD5-2 exposure results in recruitment of a favourable population of CD8 + T cells into the tumour microenvironment [20]. In OIR, the recruitment and expansion of forkhead box P3 (FOXP3) + regulatory T cells can reduce vasoobliteration, neovascularisation and vascular leakage, and alter the activation state of microglia [48]. Thus, the mechanism underlying the CD5-2-mediated effects to 'normalise' the vasculature and regulate inflammation in the eye awaits further investigation.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

et al. 2018

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Aims/hypothesis A major feature of diabetic retinopathy is breakdown of the blood-retinal barrier, resulting in macular oedema. We have developed a novel oligonucleotide-based drug, CD5-2, that specifically increases expression of the key junctional protein involved in barrier integrity in endothelial cells, vascular-endothelial-specific cadherin (VE-cadherin). CD5-2 prevents the mRNA silencing by the pro-angiogenic microRNA, miR-27a. CD5-2 was evaluated in animal models of ocular neovascularisation and vascular leak to determine its potential efficacy for diabetic retinopathy.Methods CD5-2 was tested in three mouse models of retinal dysfunction: conditional Müller cell depletion, streptozotocininduced diabetes and oxygen-induced retinopathy. Vascular permeability in the Müller cell-knockout model was assessed by fluorescein angiography. The Evans Blue leakage method was used to determine vascular permeability in streptozotocin-and oxygen-induced retinopathy models. The effects of CD5-2 on retinal neovascularisation, inter-endothelial junctions and pericyte coverage in streptozotocin-and oxygen-induced retinopathy models were determined by staining for isolectin-B4, VE-cadherin and neural/glial antigen 2 (NG2). Blockmir CD5-2 localisation in diseased retina was determined using fluorescent in situ hybridisation. The effects of CD5-2 on VE-cadherin expression and in diabetic retinopathy-associated pathways, such as the transforming growth factor beta (TGF-β) and wingless/integrated (WNT) pathway, were confirmed using western blot of lysates from HUVECs, a mouse brain endothelial cell line and a VE-cadherin null mouse endothelial cell line. Results CD5-2 penetrated the vasculature of the eye in the oxygen-induced retinopathy model. Treatment of diseased mice with CD5-2 resulted in reduced vascular leak in all three animal models, enhanced expression of VE-cadherin in the microvessels of the eye and improved pericyte coverage of the retinal vasculature in streptozotocin-induced diabetic models and oxygen-induced retinopathy models. Further, CD5-2 reduced the activation of retinal microglial cells in the streptozotocin-induced diabetic model. The positive effects of CD5-2 seen in vivo were further confirmed in vitro by increased protein expression of VEcadherin, SMAD2/3 activity, and platelet-derived growth factor B (PDGF-B). Conclusions/interpretation CD5-2 has therapeutic potential for individuals with vascular-leak-associated retinal diseases based on its ease of delivery and its ability to reverse vascular dysfunction and inflammatory aspects in three animal models of retinopathy.

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Section: Discussionmentioning

confidence: 99%

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

et al. 2018

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“…To further confirm the role of Treg in neonatal heart regeneration, we purified 1 million FOXP3 + (hCD2 + ) Treg from the spleen of NOD. Foxp3 hCD2 mice for adoptive transfer via intraperitoneal injection as previously described 20 into NOD/SCID mice so the recipients only harbored Treg without other conventional T-cells (Fig 4A). By flow cytometric analysis on day 7 following adoptive transfer, we found that about 88% of total CD3 + CD4 + T-cells were hCD2 + Treg in the spleen and heart, respectively (Fig 4B).…”

Section: Resultsmentioning

confidence: 99%

Regulatory T-cells are required for neonatal heart regeneration

et al. 2018

Preprint

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Previous work has elegantly demonstrated that, unlike adult mammalian heart, the neonatal heart is able to regenerate after injury from postnatal day (P) 1 to 7. Recently, macrophages are found to be required in the repair process as depletion of which abolishes endogenous regenerative capability of the neonatal heart. Nevertheless, whether innate immunity alone is sufficient for neonatal heart regeneration is obscure. source of chemokines and cytokines that attract monocytes and macrophages previously known to drive neonatal heart regeneration. Furthermore, Treg directly promote proliferation of both mouse and human cardiomyocytes in a paracrine manner. Our findings uncover an unappreciated mechanism in neonatal heart regeneration; and offer new avenues for developing novel therapeutics targeting Treg-mediated heart regeneration.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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“…Such cells could potentially be expanded in vitro and used for treatment. In fact, a single clone of Treg has been recently expanded in vitro and was successfully used to reduce inflammation and neovascularisation in diabetic retinopathy in mice model [30], suggesting that deciphering the clonotypic map of T-cells in AA would bring the field a step closer toward understanding the disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Alopecia areata patients show deficiency of FOXP3+CD39+ T regulatory cells and clonotypic restriction of Treg TCR?-chain, which highlights the immunopathological aspect of the disease

Åstrand¹,

Hamed²,

Bertolini³

et al. 2018

Preprint

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Alopecia areata (AA) is a hair loss disorder resulting from an autoimmune reaction against hair follicles. T-helper 1 cells are a major contributor to this disorder, but little is known about the role of T-regulatory cells (Tregs) in AA. Here, we analysed the distribution of circulating Treg subsets in twenty AA patients with active hair loss and fifteen healthy subjects by flow cytometry. The Treg suppressor HLA-DR+ subpopulation was significantly reduced in the patients (P<0.001) and there were significantly fewer cells expressing CD39 among the CD4+CD25+Foxp3+ Treg subpopulation in patients (P=0.001). FOXP3 CD39 Treg cells were also reduced in hair follicles; by 75% in non-lesional skin and 90% in lesional skin, when compared to control healthy skin. To further characterise Treg cells in AA; Tregs (CD4+CD25+FOXP3+) were investigated for their TCR sequence. PCR products analysed by Next Generation Sequencing techniques, showed that all frequent public clonotypes in AA Tregs were also present in controls at relatively similar frequencies, excepting two public clonotypes: CATSRDEGGLDEKLFF (V15 D1 J1-4) and CASRDGTGPSNYGYTF (V2 D1 J1-2), which were exclusively present in controls. This suggests that these Treg clonotypes may have a protective effect and that they may be an exciting subject for future therapeutic applications.

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Foxp3+ Tregs are recruited to the retina to repair pathological angiogenesis

Cited by 75 publications

References 55 publications

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models

Regulatory T-cells are required for neonatal heart regeneration

Alopecia areata patients show deficiency of FOXP3+CD39+ T regulatory cells and clonotypic restriction of Treg TCR?-chain, which highlights the immunopathological aspect of the disease

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