Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease

By K. Lahl, C. Loddenkemper, C. Drouin, Jennifer Freyer, J. Arnason, G. Eberl, A. Hamann, H. Wagner, J. Huehn, T. Sparwasser. Journal of Experimental Medicine, 2007

1,004 citations recorded by the source corpus.

The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3–4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome–transgenic mice termed “depletion of regulatory T cell” (DEREG) mice expressing a diphtheria toxin (DT) receptor–enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/4b3ab4dcd6a86e9f2ba1d982a4c135e17cc37412

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Citations in the corpus

Regulatory T cells and immune tolerance. (2008, background): “Recent analyses reveal that Foxp3-expressing T cells appear shortly after birth and show that the development of autoimmune/inflammatory disease follows their depletion (Kim et al., 2007; Lahl et al., 2007).”
Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. (2011, background): “DEREG mice express the diphtheria toxin receptor under control of the FoxP3+ promoter, thereby allowing the depletion of FoxP3+ cells by diphtheria toxin (DT) injection (Lahl et al., 2007).”
T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. (2012, background): “Establishment of nTreg-Me is independent of Foxp3 expression Because Foxp3 has been considered as a master regulator for Treg development, we next attempted to determine whether Foxp3 expression contributed to the establishment of nTregMe, by using DEREG (Foxp3 promoter-GFP BAC transgenic) mice and ”
Regulatory T cells exert checks and balances on self tolerance and autoimmunity (2010, background): “This does not necessarily mean that the depletion simply removes restraint on physiologically present autoimmune T cell clones specific to a particular tissue, because T reg cell depletion induces polyclonal T cell activation and systemic DC population expansion and maturatio”
Regulatory T Cells: Mechanisms of Differentiation and Function (2012, background): “A role for Treg cells in adult mice was revealed through the generation and analysis of Foxp3DTR knock-in and Foxp3-DTR BAC transgenic mice in which Treg cells are decorated with the human diphtheria toxin receptor (DTR) (35, 36).”
Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection (2009, methodology): “Indeed, selective depletion of Foxp3+ cells using mice expressing a diphtheria toxin (DT) receptor under the control of the foxp3 gene locus (Lahl et al., 2007) further enhanced effector T cell responses during nonlethal T. gondii infection (data not shown).”
A two-step process for thymic regulatory T cell development. (2008, background): “Moreover, acute depletion of Foxp3-expressing cells turns a normal resting immune system into one that is hyperactive and uncontrolled, resulting in the death of an adult animal within a mere 10 days (Kim et al., 2007; Lahl et al., 2007).”
Regulatory T Cells and Foxp3 (2011, background): “did not result in a spontaneous autoimmune inflammatory lesions, whereas Treg ablation in DEREG neonates led to a severe disease (28).”
FOXP3+ regulatory T cells in the human immune system (2010, background): “) become detectable in the periphery ∼3 days after birth, indicating that neonatal thymectomy abrogates thymic production of T Reg cell”