Cutting Edge: Broad Expression of the <i>FoxP3</i> Locus in Epithelial Cells: A Caution against Early Interpretation of Fatal Inflammatory Diseases following In Vivo Depletion of <i>FoxP3</i>-Expressing Cells

Chen, Guo‐Yun; Chen, Chong; Wang, Lizhong; Chang, Xing; Zheng, Pan; Liu, Yang

doi:10.4049/jimmunol.180.8.5163

Cited by 115 publications

(114 citation statements)

References 17 publications

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“…More recently, in support of the notion of essential role for Treg throughout the lifespan, it was reported that deletion of FoxP3-expressing cells cause acute lethal inflammation in the immune competent adult mice (22), although this finding has been disputed by another group (23). However, given our observation of FoxP3 expression in epithelial cells in mammary gland, thymus (24,25), and lung (26), it is unclear whether the cellular ablation is restricted to the Treg lineage. Expression of the FoxP3 gene in lung epithelial cells may well contribute to the lethal inflammation when high doses of diphtheria toxin was used to treat the mice in which the diphtheria toxin receptor were knocked into the FoxP3 locus.…”

Section: Homeostatic Proliferation In the Mice With Germlinecontrasting

confidence: 43%

Homeostatic Proliferation in the Mice with Germline FoxP3 Mutation and its Contribution to Fatal Autoimmunity

Chang¹,

Zheng²,

Liu

2008

The Journal of Immunology

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FoxP3 has emerged as a critical regulator for the development and function of regulatory T cells. Recent studies by several groups have demonstrated that FoxP3 is expressed outside T cell lineages. In this context, we have reported that germline mutation of FoxP3 caused defective thymopoiesis, although its potential contribution to autoimmune diseases has not been analyzed. In this study, we report that, during perinatal period, germline mutation of FoxP3 in scurfy mice caused lymphopenia in the spleen and massive homeostatic proliferation, characterized by the independence from cognate Ags and expression of bona fide markers for homeostatic proliferation. The homeostatic proliferation is suppressed by increases in T cell numbers but not by adoptive transfer of regulatory T cells (Treg). Adoptive transfer of Treg-containing bulk T cells was dramatically more effective than transfer of either Treg alone or Treg-depleted CD4 T cells in curing the scurfy mice. Our data demonstrated that FoxP3 mutation not only ablates Treg, but also dramatically increased homeostatic proliferation during the perinatal period. Homeostatic proliferation acts in concert with Treg defects in causing acute and fatal autoimmune diseases in the FoxP3 mutant mice. These results demonstrated that germline mutation of FoxP3 caused two defects that work in concert to cause lethal autoimmunity.

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Section: Homeostatic Proliferation In the Mice With Germlinecontrasting

confidence: 43%

Homeostatic Proliferation in the Mice with Germline FoxP3 Mutation and its Contribution to Fatal Autoimmunity

Chang¹,

Zheng²,

Liu

2008

The Journal of Immunology

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“…Foxp3 expression in noncancerous epithelial cells was investigated in Rag2 À/À mice, which are notably devoid of T lymphocytes, and in mice with the Scurfy mutation that deletes Foxp3 expression (Chen et al, 2008). This study revealed expression of Foxp3 mRNA and protein in the nuclei of epithelial cells in the breast, lung and prostate, but not in the liver, kidney and intestine.…”

Section: Foxp3 Expression In Normal and Cancerous Human Cellsmentioning

confidence: 98%

Human FOXP3 and cancer

et al. 2010

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FOXP3 is a transcription factor necessary and sufficient for induction of the immunosuppressive functions in regulatory T lymphocytes. Its expression was first considered as specific of this cell type, but FOXP3 can also be transiently expressed in T-cell antigen receptoractivated human nonregulatory T cells. Recent data indicate that FOXP3 is also expressed by some nonlymphoid cells, in which it can repress various oncogenes that are restored following FOXP3 deletion or mutation. This review summarizes major advances in (1) the understanding of Foxp3 functions in human regulatory T cells, (2) the prognostic significance of Foxp3-expressing T cells in human malignancies and (3) the significance of Foxp3 expression in human tumor cells.

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“…Treg are a rare subset of T cells responsible for preventing inappropriate immune responses and promoting immune tolerance (Fontenot et al, 2003;Marson et al, 2007;Feuerer et al, 2009;Josefowicz and Rudensky, 2009). Although originally thought to be T-cell-restricted, FOXP3 expression appears widespread in normal epithelia and aberrant in solid tumours, suggesting that FOXP3 can function as a tumour suppressor (Chen et al, 2008;Martin et al, 2010;Ladoire et al, 2011). As evidence, female heterozygous, Foxp3-knockout mice have a significant age-dependent increase in spontaneous mammary cancer.…”

Section: Introductionmentioning

confidence: 99%

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

et al. 2011

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The transcription factor FOXP3 has been identified as a tumour suppressor in the breast and prostate epithelia, but little is known about its specific mechanism of action. We have identified a feed-forward regulatory loop in which FOXP3 suppresses the expression of the oncogene SATB1.In particular, we demonstrate that SATB1 is not only a direct target of FOXP3 repression, but that FOXP3 also induces two miRs, miR-7 and miR-155, which specifically target the 3 0 -UTR of SATB1 to further regulate its expression. We conclude that FOXP3-regulated miRs form part of the mechanism by which FOXP3 prevents the transformation of the healthy breast epithelium to a cancerous phenotype. Approaches aimed at restoring FOXP3 function and the miRs it regulates could help provide new approaches to target breast cancer.

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Cutting Edge: Broad Expression of the FoxP3 Locus in Epithelial Cells: A Caution against Early Interpretation of Fatal Inflammatory Diseases following In Vivo Depletion of FoxP3-Expressing Cells

Cited by 115 publications

References 17 publications

Homeostatic Proliferation in the Mice with Germline FoxP3 Mutation and its Contribution to Fatal Autoimmunity

Homeostatic Proliferation in the Mice with Germline FoxP3 Mutation and its Contribution to Fatal Autoimmunity

Human FOXP3 and cancer

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

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