Feuerer, M., Hill, J. A., Mathis, D. & Benoist, C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat. Immunol. 10, 689-695

Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Immunology (Impact Factor: 20). 08/2009; 10(7):689-95. DOI: 10.1038/ni.1760
Source: PubMed


Regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 play a key role in immune homeostasis. Rather than a monomorphic population strictly determined by Foxp3 as a 'master regulator', the emerging view is one of T(reg) cells as a population with many levels of complexity. Several regulatory factors partake in the control of their transcriptional 'signature', with Foxp3 being a key regulator but insufficient and unnecessary to specify all aspects of the lineage. Distinct subphenotypes of Foxp3+ T(reg) cells are found in different anatomical locations. Some subphenotypes specifically control different facets of effector T cell function and, perhaps surprisingly, share transcriptional control elements with the very cells they regulate. This review will focus on these novel aspects of T(reg) cell diversity.

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    • "They possess functional ability to regulate both adaptive as well as innate immune responses (Jagger et al., 2014; Yamaguchi et al., 2011). iTregs can be induced (with addition of TGF-) from conventional CD25 -FOXP3 -, have a similar phenotype and exert the same suppressive functions as nTregs (Feuerer et al., 2009). While nTregs have been reported to accumulate with advancing age in frequency and absolute numbers, studies on iTregs (although much more limited) demonstrated impaired inducibility of iTregs in older individuals (Chougnet et al., 2011). "
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    ABSTRACT: The vertebrate adaptive immune system is remarkable for its possession of a very broad range of antigen receptors imbuing the system with exquisite specificity, in addition to the phagocytic and inflammatory cells of the innate system shared with invertebrates. This system requires strict control both at the level of the generation the cells carrying these receptors and at the level of their activation and effector function mediation in order to avoid autoimmunity and mitigate immune pathology. Thus, quality control checkpoints are built into the system at multiple nodes in the response, relying on clonal selection and regulatory networks to maximize pathogen-directed effects and minimize collateral tissue damage. However, these checkpoints are compromised with age, resulting in poorer immune control manifesting as tissue-damaging autoimmune and inflammatory phenomena which can cause widespread systemic disease, paradoxically compounding the problems associated with increased susceptibility to infectious disease and possibly cancer in the elderly. Better understanding the reasons for slippage of immune control will pave the way for developing rational strategies for interventions to maintain appropriate immunity while reducing immunopathology. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Feb 2015 · Ageing Research Reviews
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    • "Finally, we showed that iTregs expressed significantly higher levels of Irf4 and Tbet compared to enTregs isolated from the same inflammatory environment (Figure 4). Foxp3 works in concert with a network of transcription factors to induced full suppressive functions in Tregs [39], [40], [52]–[54]. The increased expression of Tbet may enhance iTregs to suppress the Th1 mediated inflammation in TxA23 by increasing their expression of Tbet target genes including CXCR3, CCL3, and CCL4, allowing iTregs to migrate to the site of inflammation. "
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    ABSTRACT: Strategies to boost the numbers and functions of regulatory T cells (Tregs) are currently being tested as means to treat autoimmunity. While Tregs have been shown to be effective in this role, strategies to manipulate Tregs to effectively suppress later stages of ongoing diseases need to be established. In this study, we evaluated the ability of TGF-β-induced Tregs (iTregs) specific for the major self-antigen in autoimmune gastritis to suppress established autoimmune gastritis in mice. When transferred into mice during later stages of disease, iTregs demethylated the Foxp3 promoter, maintained Foxp3 expression, and suppressed effector T cell proliferation. More importantly, these iTregs were effective at stopping disease progression. Untreated mice had high numbers of endogenous Tregs (enTregs) but these were unable to stop disease progression. In contrast, iTregs, were found in relatively low numbers in treated mice, yet were effective at stopping disease progression, suggesting qualitative differences in suppressor functions. We identified several inhibitory receptors (LAG-3, PD-1, GARP, and TNFR2), cytokines (TGF-β1 and IL12p35), and transcription factors (IRF4 and Tbet) expressed at higher levels by iTregs compared to enTregs isolated form mice with ongoing disease, which likely accounts for superior suppressor ability in this disease model. These data support efforts to use iTregs in therapies to treat establish autoimmunity, and show that iTregs are more effective than enTregs at suppressing inflammation in this disease model.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Regulatory T cells (Tregs) are a population of CD4+ T cells that play a critical role in peripheral tolerance and control of immune responses to pathogens [1]. Studies of Tregs have identified different populations of cells with immunosuppressive capabilities but with different cell surface markers, site and mode of generation [2], [3]. "
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    ABSTRACT: Regulatory T cells are a population of CD4+ T cells that play a critical role in peripheral tolerance and control of immune responses to pathogens. The purpose of this study was to measure the percentages of two different regulatory T cells subpopulations, identified by the presence or absence of CD31 (Recent thymic emigrants and peripherally induced naïve regulatory T cells), in term and preterm infant cord blood. We report the association of prenatal factors, intrauterine exposure to lipopolysaccharide and inflammation and the percentages of these regulatory T cell subpopulations in term and preterm infants. Cord blood samples were collected from both term and preterm infants and mononuclear cells isolated over a Ficoll-Hypaque cushion. Cells were then stained with fluorochrome-labeled antibodies to characterize regulatory T cell populations and analyzed with multi-color flow cytometry. Cord blood plasma C-reactive protein, and lipopolysaccharide were also measured. Placental pathology was also examined. We report a gestational age-dependent difference in the percentage of total regulatory T cells, in which preterm infants of lower gestational ages have an increased percentage of regulatory T cells. We report the presence of two populations of regulatory T cells (CD31+ and CD31-) in cord blood of term and preterm infants and their association with different maternal and fetal characteristics. Factors associated with differences in the percentage of CD31- Tregs included the use of prenatal antibiotics, steroids and magnesium sulfate. In addition, the percentage of CD31- Tregs was significantly higher in cord blood of preterm pregnancies associated with inflammation and prenatal lipopolysaccharide exposure. The peripheral Treg pool of preterm infants could be altered by prenatal exposure to inflammation and chorioamnionitis; however, the clinical implications of this finding are not yet understood.
    Full-text · Article · May 2014 · PLoS ONE
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