Overexpression of Regulatory T Cells Type 1 (Tr1) Specific Markers in a Patient with HCV-Induced Hepatocellular Carcinoma

Hepatitis C virus (HCV) is an important causative agent of liver disease, but factors that determine the resolution or progression of infection are poorly understood. In this study, we suggested that existence of immunosuppressive mechanisms, supported by regulatory T cells and especially the regulatory T cell 1 subset (Tr1), may explain the impaired immune response during infection and thus the fibrosis aggravation to hepatocellular carcinoma (HCC). Using quantitative real-time PCR, we investigated the intra-hepatic presence of Tr1 cells in biopsies from a genotype 1b infected patient followed for an 18-year period from cirrhosis to HCC. We described a significant increase of gene expression in particular for the cytokines IL-10, TGF-β, and their receptors that were perfectly correlated with an increased expression of the Tr1 specific markers (combined expression of CD4, CD18, and CD49b). This was strongly marked since the patient evolved in the pathology and could explain the failure of the treatment. In conclusion, evidence of regulatory T cell installation in the liver of chronically infected patient with cirrhosis and HCC suggests for the first time a key role for these cells in the course of HCV infection.

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Faculty Opinions recommendation of Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4942963.4875063 ◽

2010 ◽

Author(s):

Rachel R Caspi ◽

Ru Zhou

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Aryl Hydrocarbon Receptor ◽

Regulatory T Cell ◽

Human Type ◽

Aryl Hydrocarbon

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Faculty Opinions recommendation of Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell-like and Foxp3(+) regulatory T cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4942963.5880054 ◽

2010 ◽

Author(s):

Simon Robson ◽

Byron Vaughn ◽

Moritz Schmelzle

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Aryl Hydrocarbon Receptor ◽

Regulatory T Cell ◽

Human Type ◽

Aryl Hydrocarbon

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Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells

Nature Immunology ◽

10.1038/ni.1915 ◽

2010 ◽

Vol 11 (9) ◽

pp. 846-853 ◽

Cited By ~ 265

Author(s):

Roopali Gandhi ◽

Deepak Kumar ◽

Evan J Burns ◽

Meghan Nadeau ◽

Ben Dake ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Aryl Hydrocarbon Receptor ◽

Regulatory T Cell ◽

Human Type ◽

Aryl Hydrocarbon

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Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/13524585211003301 ◽

2021 ◽

pp. 135245852110033

Author(s):

Quentin Howlett-Prieto ◽

Xuan Feng ◽

John F Kramer ◽

Kevin J Kramer ◽

Timothy W Houston ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

B Cell ◽

Regulatory T Cell ◽

Healthy Controls ◽

Regulatory Cells ◽

Long Term Treatment ◽

Anti Cd20

Objective: To determine the effect of long-term anti-CD20 B-cell-depleting treatment on regulatory T cell immune subsets that are subnormal in untreated MS patients. Methods: 30 clinically stable MS patients, before and over 38 months of ocrelizumab treatment, were compared to 13 healthy controls, 29 therapy-naïve MS, 9 interferon-β-treated MS, 3 rituximab-treated MS, and 3 rituximab-treated patients with other autoimmune inflammatory diseases. CD8, CD28, CD4, and FOXP3 expression in peripheral blood mononuclear cells was quantitated with flow cytometry. Results: CD8+ CD28− regulatory cells rose from one-third of healthy control levels before ocrelizumab treatment (2.68% vs 7.98%), normalized by 12 months (13.5%), and rose to 2.4-fold above healthy controls after 18 months of ocrelizumab therapy (19.0%). CD4+ FOXP3+ regulatory cells were lower in MS than in healthy controls (7.98%) and showed slight long-term decreases with ocrelizumab. CD8+ CD28− and CD4+ FOXP3+ regulatory T cell percentages in IFN-β-treated MS patients were between those of untreated MS and healthy controls. Interpretation: Long-term treatment with ocrelizumab markedly enriches CD8+ CD28− regulatory T cells and corrects the low levels seen in MS before treatment, while slightly decreasing CD4+ FOXP3+ regulatory T cells. Homeostatic enrichment of regulatory CD8 T cells provides a mechanism, in addition to B cell depletion, for the benefits of anti-CD20 treatment in MS.

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Multiply restimulated human thymic regulatory T cells express distinct signature regulatory T-cell transcription factors without evidence of exhaustion

Cytotherapy ◽

10.1016/j.jcyt.2021.02.118 ◽

2021 ◽

Author(s):

Keli L. Hippen ◽

Scott N. Furlan ◽

Rahul Roychoudhuri ◽

Ena Wang ◽

Yigang Zhang ◽

...

Keyword(s):

T Cells ◽

Transcription Factors ◽

T Cell ◽

Regulatory T Cells ◽

Regulatory T Cell

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Regulatory T Cells Contribute to Resistance against Lyme Arthritis

Infection and Immunity ◽

10.1128/iai.00160-20 ◽

2020 ◽

Vol 88 (11) ◽

Author(s):

Emily M. Siebers ◽

Elizabeth S. Liedhegner ◽

Michael W. Lawlor ◽

Ronald F. Schell ◽

Dean T. Nardelli

Keyword(s):

T Cells ◽

T Cell ◽

Lyme Disease ◽

Regulatory T Cells ◽

Regulatory T Cell ◽

Interleukin 10 ◽

Lyme Arthritis ◽

Interleukin 17 ◽

Content Type

ABSTRACT The symptoms of Lyme disease are caused by inflammation induced by species of the Borrelia burgdorferi sensu lato complex. The various presentations of Lyme disease in the population suggest that differences exist in the intensity and regulation of the host response to the spirochete. Previous work has described correlations between the presence of regulatory T cells and recovery from Lyme arthritis. However, the effects of Foxp3-expressing CD4+ T cells existing prior to, and during, B. burgdorferi infection have not been well characterized. Here, we used C57BL/6 “depletion of regulatory T cell” mice to assess the effects these cells have on the arthritis-resistant phenotype characteristic of this mouse strain. We showed that depletion of regulatory T cells prior to infection with B. burgdorferi resulted in sustained swelling, as well as histopathological changes, of the tibiotarsal joints that were not observed in infected control mice. Additionally, in vitro stimulation of splenocytes from these regulatory T cell-depleted mice resulted in increases in gamma interferon and interleukin-17 production and decreases in interleukin-10 production that were not evident among splenocytes of infected mice in which Treg cells were not depleted. Depletion of regulatory T cells at various times after infection also induced rapid joint swelling. Collectively, these findings provide evidence that regulatory T cells existing at the time of, and possibly after, B. burgdorferi infection may play an important role in limiting the development of arthritis.

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Thymic Regulatory T Cell Development: Role of Signalling Pathways and Transcription Factors

Clinical and Developmental Immunology ◽

10.1155/2013/617595 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 9

Author(s):

Mark Engel ◽

Tom Sidwell ◽

Ajithkumar Vasanthakumar ◽

George Grigoriadis ◽

Ashish Banerjee

Keyword(s):

T Cells ◽

Transcription Factors ◽

T Cell ◽

Regulatory T Cells ◽

Immune Tolerance ◽

Regulatory T Cell ◽

T Cell Development ◽

Signalling Pathways ◽

Treg Development

Regulatory T cells (Tregs) are a subset of CD4 T cells that are key mediators of immune tolerance. Most Tregs develop in the thymus. In this review we summarise recent findings on the role of diverse signalling pathways and downstream transcription factors in thymic Treg development.

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Abrogation of CD40–CD154 Signaling Impedes the Homeostasis of Thymic Resident Regulatory T Cells by Altering the Levels of IL-2, but Does Not Affect Regulatory T Cell Development

The Journal of Immunology ◽

10.4049/jimmunol.1200588 ◽

2012 ◽

Vol 189 (4) ◽

pp. 1717-1725 ◽

Cited By ~ 17

Author(s):

Steven M. Cuss ◽

E. Allison Green

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Regulatory T Cell ◽

T Cell Development ◽

Cell Development

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Increased islet antigen–specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes–protective haplotype

Science Immunology ◽

10.1126/sciimmunol.aax8767 ◽

2020 ◽

Vol 5 (44) ◽

pp. eaax8767 ◽

Cited By ~ 3

Author(s):

Xiaomin Wen ◽

Junbao Yang ◽

Eddie James ◽

I-Ting Chow ◽

Helena Reijonen ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Regulatory T Cells ◽

Interleukin 4 ◽

Specific Class ◽

Protective Haplotype ◽

Specific Effector ◽

Islet Antigen

The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, but the cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- and DQ6-restricted glutamate decarboxylase 65 (GAD65) and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP)–specific T cell epitopes. Three of the DR1501/DQ6-restricted epitopes identified were previously reported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramer reagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+CD127−FOXP3+ regulatory CD4+ T cells were present at higher frequencies in individuals with the protective haplotype than those with susceptible or neutral haplotypes. We further confirmed higher frequencies of islet antigen–specific effector and regulatory CD4+ T cells in DR1501-DQ6 individuals through a CD154/CD137 up-regulation assay. DR1501-restricted effector T cells were capable of producing interferon-γ (IFN-γ) and interleukin-4 (IL-4) but were more likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluate their capacity for antigen-specific regulatory activity, we cloned GAD65 and IGRP epitope–specific regulatory T cells. We showed that these regulatory T cells suppressed DR1501-restricted GAD65- and IGRP-specific effectors and DQB1*03:02-restricted GAD65-specific effectors in an antigen-specific fashion. In total, these results suggest that the protective DR1501-DQ6 haplotype confers protection through increased frequencies of islet-specific IL-10–producing T effectors and CD25+CD127−FOXP3+ regulatory T cells.

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