Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT

BackgroundNon-infectious uveitis can cause chronic relapsing and remitting ocular inflammation, which may require high dose systemic immunosuppression to prevent severe sight loss. It has been classically described as an autoimmune disease, mediated by pro-inflammatory Th1 and Th17 T-cell subsets. S...

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Main Authors: Rose M. Gilbert, Xiaozhe Zhang, Robert D. Sampson, Michael R. Ehrenstein, Dao X. Nguyen, Mahid Chaudhry, Charles Mein, Nadiya Mahmud, Grazyna Galatowicz, Oren Tomkins-Netzer, Virginia L. Calder, Sue Lightman
Format: Article
Language:English
Published: Frontiers Media S.A. 2018-05-01
Series:Frontiers in Immunology
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Online Access:http://journal.frontiersin.org/article/10.3389/fimmu.2018.00907/full
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author Rose M. Gilbert
Rose M. Gilbert
Xiaozhe Zhang
Xiaozhe Zhang
Robert D. Sampson
Michael R. Ehrenstein
Dao X. Nguyen
Mahid Chaudhry
Charles Mein
Nadiya Mahmud
Grazyna Galatowicz
Oren Tomkins-Netzer
Oren Tomkins-Netzer
Virginia L. Calder
Sue Lightman
Sue Lightman
spellingShingle Rose M. Gilbert
Rose M. Gilbert
Xiaozhe Zhang
Xiaozhe Zhang
Robert D. Sampson
Michael R. Ehrenstein
Dao X. Nguyen
Mahid Chaudhry
Charles Mein
Nadiya Mahmud
Grazyna Galatowicz
Oren Tomkins-Netzer
Oren Tomkins-Netzer
Virginia L. Calder
Sue Lightman
Sue Lightman
Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT
Frontiers in Immunology
uveitis
T-regulatory cells
TIGIT
T-bet
ocular inflammation
remission
author_facet Rose M. Gilbert
Rose M. Gilbert
Xiaozhe Zhang
Xiaozhe Zhang
Robert D. Sampson
Michael R. Ehrenstein
Dao X. Nguyen
Mahid Chaudhry
Charles Mein
Nadiya Mahmud
Grazyna Galatowicz
Oren Tomkins-Netzer
Oren Tomkins-Netzer
Virginia L. Calder
Sue Lightman
Sue Lightman
author_sort Rose M. Gilbert
title Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT
title_short Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT
title_full Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT
title_fullStr Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT
title_full_unstemmed Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT
title_sort clinical remission of sight-threatening non-infectious uveitis is characterized by an upregulation of peripheral t-regulatory cell polarized towards t-bet and tigit
publisher Frontiers Media S.A.
series Frontiers in Immunology
issn 1664-3224
publishDate 2018-05-01
description BackgroundNon-infectious uveitis can cause chronic relapsing and remitting ocular inflammation, which may require high dose systemic immunosuppression to prevent severe sight loss. It has been classically described as an autoimmune disease, mediated by pro-inflammatory Th1 and Th17 T-cell subsets. Studies suggest that natural immunosuppressive CD4+CD25+FoxP3+ T-regulatory cells (Tregs) are involved in resolution of inflammation and may be involved in the maintenance of clinical remission.ObjectiveTo investigate whether there is a peripheral blood immunoregulatory phenotype associated with clinical remission of sight-threatening non-infectious uveitis by comparing peripheral blood levels of Treg, Th1, and Th17, and associated DNA methylation and cytokine levels in patients with active uveitic disease, control subjects and patients (with previously active disease) in clinical remission induced by immunosuppressive drugs.MethodsIsolated peripheral blood mononuclear cells (PBMC) from peripheral blood samples from prospectively recruited subjects were analyzed by flow cytometry for CD3, CD4, FoxP3, TIGIT, T-bet, and related orphan receptor γt. Epigenetic DNA methylation levels of FOXP3 Treg-specific demethylated region (TSDR), FOXP3 promoter, TBX21, RORC2, and TIGIT loci were determined in cryopreserved PBMC using a next-generation sequencing approach. Related cytokines were measured in blood sera. Functional suppressive capacity of Treg was assessed using T-cell proliferation assays.ResultsFifty patients with uveitis (intermediate, posterior, and panuveitis) and 10 control subjects were recruited. The frequency of CD4+CD25+FoxP3+ Treg, TIGIT+ Treg, and T-bet+ Treg and the ratio of Treg to Th1 were significantly higher in remission patients compared with patients with active uveitic disease; and TIGIT+ Tregs were a significant predictor of clinical remission. Treg from patients in clinical remission demonstrated a high level of in vitro suppressive function compared with Treg from control subjects and from patients with untreated active disease. PBMC from patients in clinical remission had significantly lower methylation levels at the FOXP3 TSDR, FOXP3 promoter, and TIGIT loci and higher levels at RORC loci than those with active disease. Clinical remission was also associated with significantly higher serum levels of transforming growth factor β and IL-10, which positively correlated with Treg levels, and lower serum levels of IFNγ, IL-17A, and IL-22 compared with patients with active disease.ConclusionClinical remission of sight-threatening non-infectious uveitis has an immunoregulatory phenotype characterized by upregulation of peripheral Treg, polarized toward T-bet and TIGIT. These findings may assist with individualized therapy of uveitis, by informing whether drug therapy has induced phenotypically stable Treg associated with long-term clinical remission.
topic uveitis
T-regulatory cells
TIGIT
T-bet
ocular inflammation
remission
url http://journal.frontiersin.org/article/10.3389/fimmu.2018.00907/full
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spelling doaj-b42b99a840f043ffb206c156e89239dc2020-11-24T22:51:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-05-01910.3389/fimmu.2018.00907315732Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGITRose M. Gilbert0Rose M. Gilbert1Xiaozhe Zhang2Xiaozhe Zhang3Robert D. Sampson4Michael R. Ehrenstein5Dao X. Nguyen6Mahid Chaudhry7Charles Mein8Nadiya Mahmud9Grazyna Galatowicz10Oren Tomkins-Netzer11Oren Tomkins-Netzer12Virginia L. Calder13Sue Lightman14Sue Lightman15Ocular Immunology, Institute of Ophthalmology, University College London (UCL), London, United KingdomMoorfields Eye Hospital NHS Foundation Trust, London, United KingdomOcular Immunology, Institute of Ophthalmology, University College London (UCL), London, United KingdomMoorfields Eye Hospital NHS Foundation Trust, London, United KingdomFlow Cytometry Core Facility, Institute of Ophthalmology, University College London (UCL), London, United KingdomDivision of Medicine, Centre for Rheumatology, University College London (UCL), London, United KingdomDivision of Medicine, Centre for Rheumatology, University College London (UCL), London, United KingdomOcular Immunology, Institute of Ophthalmology, University College London (UCL), London, United KingdomGenome Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomGenome Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomOcular Immunology, Institute of Ophthalmology, University College London (UCL), London, United KingdomOcular Immunology, Institute of Ophthalmology, University College London (UCL), London, United KingdomMoorfields Eye Hospital NHS Foundation Trust, London, United KingdomOcular Immunology, Institute of Ophthalmology, University College London (UCL), London, United KingdomOcular Immunology, Institute of Ophthalmology, University College London (UCL), London, United KingdomMoorfields Eye Hospital NHS Foundation Trust, London, United KingdomBackgroundNon-infectious uveitis can cause chronic relapsing and remitting ocular inflammation, which may require high dose systemic immunosuppression to prevent severe sight loss. It has been classically described as an autoimmune disease, mediated by pro-inflammatory Th1 and Th17 T-cell subsets. Studies suggest that natural immunosuppressive CD4+CD25+FoxP3+ T-regulatory cells (Tregs) are involved in resolution of inflammation and may be involved in the maintenance of clinical remission.ObjectiveTo investigate whether there is a peripheral blood immunoregulatory phenotype associated with clinical remission of sight-threatening non-infectious uveitis by comparing peripheral blood levels of Treg, Th1, and Th17, and associated DNA methylation and cytokine levels in patients with active uveitic disease, control subjects and patients (with previously active disease) in clinical remission induced by immunosuppressive drugs.MethodsIsolated peripheral blood mononuclear cells (PBMC) from peripheral blood samples from prospectively recruited subjects were analyzed by flow cytometry for CD3, CD4, FoxP3, TIGIT, T-bet, and related orphan receptor γt. Epigenetic DNA methylation levels of FOXP3 Treg-specific demethylated region (TSDR), FOXP3 promoter, TBX21, RORC2, and TIGIT loci were determined in cryopreserved PBMC using a next-generation sequencing approach. Related cytokines were measured in blood sera. Functional suppressive capacity of Treg was assessed using T-cell proliferation assays.ResultsFifty patients with uveitis (intermediate, posterior, and panuveitis) and 10 control subjects were recruited. The frequency of CD4+CD25+FoxP3+ Treg, TIGIT+ Treg, and T-bet+ Treg and the ratio of Treg to Th1 were significantly higher in remission patients compared with patients with active uveitic disease; and TIGIT+ Tregs were a significant predictor of clinical remission. Treg from patients in clinical remission demonstrated a high level of in vitro suppressive function compared with Treg from control subjects and from patients with untreated active disease. PBMC from patients in clinical remission had significantly lower methylation levels at the FOXP3 TSDR, FOXP3 promoter, and TIGIT loci and higher levels at RORC loci than those with active disease. Clinical remission was also associated with significantly higher serum levels of transforming growth factor β and IL-10, which positively correlated with Treg levels, and lower serum levels of IFNγ, IL-17A, and IL-22 compared with patients with active disease.ConclusionClinical remission of sight-threatening non-infectious uveitis has an immunoregulatory phenotype characterized by upregulation of peripheral Treg, polarized toward T-bet and TIGIT. These findings may assist with individualized therapy of uveitis, by informing whether drug therapy has induced phenotypically stable Treg associated with long-term clinical remission.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00907/fulluveitisT-regulatory cellsTIGITT-betocular inflammationremission