Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

Seddiki, Nabila; Santner-Nanan, Brigitte; Martinson, Jeff; Zaunders, John; Sasson, Sarah C.; Landay, Alan; Solomon, Michael J.; Selby, Warwick; Alexander, Stephen I.; Nanan, Ralph; Kelleher, Anthony D.; Groth, Barbara Fazekas de St

doi:10.1084/jem.20060468

Cited by 1,353 publications

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“…1A. For CD127 À Treg cell isolation, the gating strategy suggested by Seddiki et al [19] and Liu et al [20] was used, whereby CD4 1 CD25 1 cells with FSc/SSc characteristics of lymphocytes and with low CD127 expression level were sorted (Fig. 1B) Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we aimed to clarify these issues with the help of two recent advances in the field: First, we recently described that natural Treg differ from other T-cell populations in their DNA methylation status of a defined region within the FOXP3 locus termed Treg-specific demethylation region (TSDR): Demethylation of this region is exclusively observed in natural Treg, but neither in activated Tconv cells nor in TGF-b-induced Treg [17,18]. Second, the groups of Fazekas de Saint Groth and Bluestone reported that human CD4 1 CD25 1 Treg can be distinguished from activated (and thus also CD25 1 ) Tconv cells by their different surface expression levels of CD127 (IL-7 receptor a-chain, IL-7Ra): whereas activated Tconv cells are strongly positive for CD127, Treg show only low or no expression of this marker [19,20]. Thus, sorting of CD4 1 CD25 1 CD127 low/neg T cells (CD127 À Treg) should minimize contamination of the starting population with Tconv cells and this increased purity should result in homogeneous Treg cell products after expansion.…”

Section: Introductionmentioning

confidence: 99%

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Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

et al. 2009

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The adoptive transfer of CD4 1 CD25 1 natural regulatory T cells (Treg) is a promising strategy for the treatment of autoimmune diseases and the prevention of alloresponses after transplantation. Clinical trials exploring this strategy require efficient in vitro expansion of this rare cell population. Protocols developed thus far rely on high-grade purification of Treg prior to culture initiation, a process still hampered by the lack of Treg cell-specific surface markers. Depletion of CD127 1 cells was shown to separate activated conventional T cells from natural Treg cell populations allowing the isolation of highly enriched FOXP3 1 cells with all functional and molecular characteristics of natural Treg. Here, we demonstrate that upon in vitro expansion, CpG methylation in a conserved region within the FOXP3 gene locus increased in CD4 1 CD25 1 CD127 low Treg, correlating with loss of FOXP3 expression and emergence of pro-inflammatory cytokines. Further analysis identified CD45RA À FOXP3 1 memory-type Treg as the main source of converting cells, whereas CD45RA 1 FOXP3 1 Treg from the same donors showed no conversion within 3 wk of in vitro expansion. Thus, Treg cell lineage differentiation does not seem to represent a final fate decision, as natural Treg can lose their cell-type-specific characteristics after repetitive TCR stimulation.Key words: Cellular therapy . Immune regulation . Treg Supporting Information available online Introduction CD4 1 CD25 1 Treg are pivotal for the maintenance of peripheral self-tolerance and imbalances in this T-cell compartment have been shown to contribute to various autoimmune diseases [1]. In murine disease models, adoptively transferred Treg prevent, and in some cases, even cure autoimmunity [2,3]. In addition, they protect from graft rejection after allogeneic organ transplantation [4] as well as from graft-versus-host disease after MHCmismatched stem cell transplantation [5][6][7][8]. Recently, a limited number of Phase I clinical trials exploring the adoptive transfer of Treg have been initiated and several additional trials in various clinical settings are in preparation [9,10]. Prerequisites for the initiation of such trials are (i) the availability of efficient in vitro expansion protocols for this rare cell population and (ii) the ability to unequivocally identify Treg to avoid contamination of 1088Treg cultures with potentially harmful conventional effector T cells (Tconv). While efficient cell culture protocols have recently been established by us and others for the polyclonal as well as antigen-specific Treg cell expansion [11][12][13], the search for an exclusive surface marker for Treg is still ongoing.Contrary to earlier reports, human CD4 1 CD25 high Treg in adult peripheral blood have recently been shown to comprise not only (self-)antigen-experienced, CD45RA À central and effector memory cells, but also a subpopulation of CD45RA 1 naïve recent thymic emigrants [14,15]. We previously demonstrated that these CD45RA 1 CD4 1 CD25 high T cells (RA 1 Treg) homogen...

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

et al. 2009

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“…This definition of T reg has been well established in samples from healthy controls. 16,17 We validated correct T reg identification within CD3-positive/CD4-positive/CD25-positive/CD127-negative cells in a subgroup of patients with CLL by detecting high intracellular expression levels of FoxP3 and the ability to suppress Tcell proliferation (Fig. 1).…”

Section: Definition and Stability Of T Regs In Cllmentioning

confidence: 95%

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Weiß

Melchardt

Egle

et al. 2010

Cancer

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BACKGROUND: Early stage chronic lymphocytic leukemia is characterized by a highly variable course of disease. Because it is believed that regulatory T cells (T regs ) are potent suppressors of antitumor immunity, the authors hypothesized that increased T regs may favor disease progression. METHODS: T reg levels (cluster of differentiation 3 [CD3]-positive, [CD4]-positive, CD25-positive, and CD127-negative) in peripheral blood from 102 patients were analyzed by flow cytometry. Statistical analysis was used to evaluate correlations with clinical data. RESULTS: The relative T reg numbers in CD4-positive T cells were significantly greater in patients with chronic lymphocytic leukemia compared with the numbers in a control group of 170 healthy individuals (P ¼ .001). Patients were divided into 2 groups using a median T reg value of 9.7% (the percentage of CD4-positive T cells). Patients with higher T reg levels had a significantly shorter time to initial treatment (median, 5.9 years) compared with patients who had lower T reg levels (median, 11.7 years; log-rank P ¼ .019). Furthermore, T reg levels (the percentage of CD4-positive T cells) had significant prognostic power to predict the time to initial treatment in univariate analysis (P ¼ .023) and in multivariate Cox regression analysis that included the variables Rai stage, immunoglobulin heavy-chain variable region gene mutational status, chromosomal aberrations, and CD38 expression (P ¼ .028). CONCLUSIONS: Higher T reg levels had significant and independent prognostic power for predicting the time to initial treatment in patients with low to intermediate stage chronic lymphocytic leukemia.

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“…Following recent reports that suggested measuring the expression of CD127 (22) (down-regulated by FoxP3) and C45RA (23,24) as adjuncts to Treg cell identification, we evaluated the correlation between expression of these markers and expression of CD25 high and FoxP3 cells. We found good correlations between these different methods of identifying Treg cells in our study population (data not shown).…”

Section: Decreasedmentioning

confidence: 99%

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

Landau¹,

Rosenzwajg²,

Saadoun³

et al. 2008

Arthritis & Rheumatism

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Objective. Mixed cryoglobulinemia (MC) vasculitis is an autoimmune disorder associated with chronic hepatitis C virus (HCV) infection. We previously reported that MC vasculitis is associated with a quantitative defect of peripheral blood regulatory T cells. The aim of this study was to prospectively evaluate the evolution of this defect during the course of antiviral treatment.Methods. Treg cell frequencies and numbers were analyzed in 131 patients with chronic HCV infection (including 66 with MC vasculitis) and 20 healthy volunteer donors. Measurements were taken before, during, and after treatment with PEGylated interferon alfa-2b plus ribavirin.Results. At baseline, patients with MC vasculitis had a significantly lower frequency and number of Treg cells than did patients without MC vasculitis. Complete remission of MC vasculitis following antiviral treatment was associated with a significant increase in Treg cell levels compared with baseline. In contrast, Treg cell levels in nonresponders or partial responders, which did not differ from those in complete responders at baseline, remained unchanged over the course of the study. Conclusion. The strong positive correlation between clinical responses and Treg cell levels provides further support for the central role of Treg cells in the pathogenesis of HCV-induced MC vasculitis and emphasizes the dual role of Treg cells in chronic HCV infection: while Treg cells may hinder viral elimination, they also limit autoimmune injury.Chronic infection with hepatitis C virus (HCV) is the main cause of mixed cryoglobulinemia (MC) vasculitis, a potentially life-threatening systemic vasculitis (1). MC is a B cell proliferative disorder characterized by polyclonal or monoclonal activation and autoantibody production. MC may lead to clinical manifestations ranging from an MC syndrome (purpura, arthralgia, asthenia) to a more serious vasculitis with nervous system and renal involvement (1). The observation of T cells in the vascular infiltrates and the presence of autoantibodies, together with the observation that some HLA groups confer susceptibility to MC vasculitis in HCV-infected patients, suggest that autoimmune processes are implied in this virus-induced disease (2,3). It has been demonstrated that antiviral treatment can lead to the disappearance of symptoms and can induce an immunologic response, i.e., a significant decrease in plasma cryoglobulin levels (4). Furthermore, the clinical response is closely related to effective viral elimination (4,5), supporting the causal link between chronic HCV infection and the autoimmune process.During the past several years, CD4ϩCD25 high immunoregulatory T cells have been identified in

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Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

Cited by 1,353 publications

References 30 publications

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

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Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

Cited by 1,353 publications

References 30 publications

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Regulatory T cells predict the time to initial treatment in early stage chronic lymphocytic leukemia

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

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Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation