X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

Wildin, Robert S.; Ramsdell, Fred; Peake, Jane; Faravelli, Francesca; Casanova, Jean‐Laurent; Buist, Neil R. M.; Levy-Lahad, Ephrat; Mazzella, Massimo; Goulet, Olivier; Perroni, L; Bricarelli, Franca Dagna; Byrne, G C; McEuen, Mark; Proll, Sean; Appleby, Mark W.; Brunkow, Mary E.

doi:10.1038/83707

Cited by 1,655 publications

(1,176 citation statements)

References 11 publications

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“…Since its identification as the key transcription factor for the formation and function of Treg in mouse and humans,23, 31, 32 FOXP3 has been the subject of much investigation. Molecular mechanisms for the action of FOXP3 in shaping regulatory T cells and their critical role in maintaining lifelong tolerance are now being better understood.…”

Section: Transcriptional Control Of Treg Formation and Functionmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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Section: Transcriptional Control Of Treg Formation and Functionmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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“…FoxP3 + CD4 + Treg cells play an important role in the regulation of humoral immune responses, as both mice and humans lacking FoxP3 have elevated levels of circulating antibodies 232, 233. By regulating initial CD4 + T‐cell activation and differentiation FoxP3 + CD4 + Treg cells can reduce the initial generation of Tfh cells, although they may also enhance CD4 + T‐cell differentiation into Tfh cells by sequestering IL‐2 234.…”

Section: Regulatory Cell Populations and Their Relationship To Bnab Imentioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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“…In humans, Foxp3 mutations were shown to cause the immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) [6,7]. Since then, Foxp3 has been frequently used as a Treg marker in murine and human studies.…”

Section: Introductionmentioning

confidence: 99%

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells

Aarts-Riemens¹,

Emmelot²,

Verdonck³

et al. 2008

Eur J Immunol

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The forkhead/winged helix transcription factor (Foxp3) is expressed as two different isoforms in humans: the full-length isoform (Foxp3FL) and an alternative-splicing product lacking the exon 2 (Foxp3DE2). We here studied the cellular distribution of Foxp3 isoforms by quantitative PCR and evaluated the functional outcome of retroviral transduction of Foxp3FL and Foxp3DE2 genes into CD4 + CD25 -cells. In PBMC, both isoforms were preferentially expressed in CD4 + CD25 hi cells. In single-cell-sorted and expanded Treg, both Foxp3 isoforms were expressed simultaneously but without a fixed ratio. Forced expression of Foxp3FL or Foxp3DE2 genes in CD4 + CD25 -T cells induced bona fide Treg that not only displayed Treg phenotype but also were anergic and mediated significant suppressive activity against CD3-activated CD4 + CD25 -cells. GFP -nontransduced cells or cells transduced with an empty vector showed no Treg phenotype, anergy or suppressive activities. In conclusion, our results reveal that both Foxp3 isoforms possess similar capacities to induce Treg; however, unnaturally high expression levels are required to convey Treg functions to CD4 + CD25 -cells. As both Foxp3 isoforms appear to be expressed in an independent fashion, studies aiming at quantification of Treg in peripheral blood or in tissue samples can benefit from determination of total Foxp3 levels rather than one of the isoforms.

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X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

Cited by 1,655 publications

References 11 publications

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells

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X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

Cited by 1,655 publications

References 11 publications

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25– cells

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Product

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Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells