The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.

Lyon, Mary F.; Peters, Jo; Glenister, P. H.; Ball, Simon; Wright, E.M.

doi:10.1073/pnas.87.7.2433

Cited by 160 publications

(113 citation statements)

References 15 publications

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“…Mutations of FOXP3 in humans lead to an early-onset, multisystem autoimmune syndrome known as IPEX (immune dysregulation, polyendocrinopathy, enteropathy, Xlinked) (5-7). Foxp3 null and scurfy mice exhibit an analogous autoimmune pathology (8,9), suggesting that a similar function is served by FOXP3 across phylogeny.…”

Section: Fig 1 Flow Cytometric Detection Of Foxp3 In Murine and Hummentioning

confidence: 99%

Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development

Gavin¹,

Torgerson

Houston³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

704

579

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Forkhead winged-helix transcription factor Foxp3 serves as the dedicated mediator of the genetic program governing CD25 + CD4 + regulatory T cell (T r ) development and function in mice. In humans, its role in mediating T r development has been controversial. Furthermore, the fate of T r precursors in FOXP3 deficiency has yet to be described. Making use of flow cytometric detection of human FOXP3, we have addressed the relationship between FOXP3 expression and human T r development. Unlike murine Foxp3 − T cells, a small subset of human CD4 + and CD8 + T cells transiently up-regulated FOXP3 upon in vitro stimulation. Induced FOXP3, however, did not alter cell-surface phenotype or suppress T helper 1 cytokine expression. Furthermore, only ex vivo FOXP3 + T r cells persisted after prolonged culture, suggesting that induced FOXP3 did not activate a T r developmental program in a significant number of cells. FOXP3 flow cytometry was also used to further characterize several patients exhibiting symptoms of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) with or without FOXP3 mutations. Most patients lacked FOXP3-expressing cells, further solidifying the association between FOXP3 deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Interestingly, one patient bearing a FOXP3 mutation enabling expression of stable FOXP3 mut protein exhibited FOXP3 mut -expressing cells among a subset of highly activated CD4 + T cells. This observation raises the possibility that the severe autoimmunity in FOXP3 deficiency can be attributed, in part, to aggressive T helper cells that have developed from T r precursors.

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Section: Fig 1 Flow Cytometric Detection Of Foxp3 In Murine and Hummentioning

confidence: 99%

Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development

Gavin¹,

Torgerson

Houston³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

704

579

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“…Scurfy is associated with hypergammaglobulinaemia, low platelet and erythrocyte counts, and mice die from wasting syndrome secondary to overproduction of cytokines. Scurfy resembles WiskottAldrich syndrome in humans [178]. Both central (thymic) and peripheral tolerance are defective in Scurfy mice [179].…”

Section: ªMonogenicº Diabetes Syndromesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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“…5). Overall, FILIG/Y mice displayed phenotypes reminiscent of scurfy mice 13 and T-cellspecific Foxp3 knockout mice 1 . To investigate whether transcription of the endogenous Foxp3 gene was abolished in FILIG mice, we first detected luciferase expression by live imagining.…”

mentioning

confidence: 99%

Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression

Wan

Flavell

2007

Nature

775

661

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The naturally occurring regulatory T cell (T R ) is the pivotal cell type that maintains self-tolerance and exerts active immune suppression. The development and function of T R cells is controlled by Foxp3 (refs 1, 2), a lack of which results in loss of T R cells and massive multi-organ autoimmunity in scurfy mice and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients 3,4 . It is generally thought that, through a binary mechanism, Foxp3 expression serves as an on-and-off switch to regulate positively the physiology of T R cells; however, emerging evidence associates decreased Foxp3 expression in T R cells with various immune disorders [5][6][7] . We hypothesized that Foxp3 regulates T R cell development and function in a dose-dependent, nonbinary manner, and that decreased Foxp3 expression can cause immune disease. Here, by generating a mouse model in which endogenous Foxp3 gene expression is attenuated in T R cells, we show that decreased Foxp3 expression results in the development of an aggressive autoimmune syndrome similar to that of scurfy mice, but does not affect thymic development, homeostatic expansion/maintenance or transforming-growth-factor-b-induced de novo generation of Foxp3-expressing cells. The immunesuppressive activities of T cells with attenuated Foxp3 expression were nearly abolished in vitro and in vivo, whereas their anergic properties in vitro were maintained. This was accompanied by decreased expression of T R cell 'signature genes'. Notably, T cells expressing decreased Foxp3 preferentially became T-helper 2 (T H 2)-type effectors even in a T H 1-polarizing environment. These cells instructed T H 2 differentiation of conventional T cells, which contributed to the immune diseases observed in these mice. Thus, decreased Foxp3 expression causes immune disease by subverting the suppressive function of T R cells and converting T R cells into effector cells; these findings are important for understanding the regulation of T R cell function and the aetiology of various human immune diseases.T R cells, a central component for immune suppression, are critical for establishing self-tolerance, controlling inflammatory responses and maintaining immune homeostasis 8,9 . Foxp3, an X-chromosome-linked factor that controls T R cell development and function 1,2 , is generally thought to control positively the functions of T R cells in a binary fashion, as Foxp3 expression is sufficient to specify immune-suppressive activities in conventional T cells 1,2,10 . Thus, current efforts are focused on associating abnormal numbers of T R cells with immune disorders. However, the quality of T R cells is also critical for their function 11 . We observed lowered levels of Foxp3 in intra-islet T R cells compared with T R cells from other peripheral lymphoid organs in diabetic NOD mice (Fig. 1a), whereas the frequencies of Foxp3-expressing T R cells among different compartments were comparable (data not shown). However, such a specific decrease in Foxp3 expression was not observed in no...

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The scurfy mouse mutant has previously unrecognized hematological abnormalities and resembles Wiskott-Aldrich syndrome.

Cited by 160 publications

References 15 publications

Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development

Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development

Genetic control of autoimmunity in Type I diabetes and associated disorders

Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression

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