The original scurfy (sf) mutation, a fatal X-linked condition, has occurred spontaneously in a partially inbred strain of mice (Russell et al. 1959). Shortly after birth, affected male mice present with a scaly skin rash and severe runting secondary to chronic diarrhea and malabsorption. Characteristically, the mice exhibited lymphadenopathy, splenomegaly, massive lymphocytic infiltrates of the skin, liver, and lungs and developed hemolytic anemia associated with a positive Coombs test, suggesting that the sf mutation causes a generalized autoimmune-like syndrome. The gene responsible for the sf mutation was identified and designated as Foxp3 (Brunkow et al. 2001) consisting of a two-base-pair insertion in exon 8, resulting in a frame shift that leads to a truncated protein product lacking the carboxy-terminal fork-head domain. This sf mouse model was instrumental in the discovery of Treg cells (Fontenot et al. 2003). Using Foxp3-negative gene-targeted mice and a GFP-Foxp3 fusion-protein-reporter knock-in allele, it could be shown that expression of Foxp3 was highly restricted to ap CD4+ T cells and irrespective of CD25 expression correlated with suppressor activity (Fontenot et al. 2005). Acute in vivo ablation of Treg cells demonstrated that Treg cells play vital function in neonatal and adult mice suggesting that self-reactive T cells are continuously suppressed by Treg cells. When this suppression is relieved, self-reactive T cells become activated and facilitate accelerated maturation of dendritic cells and events that lead to catastrophic autoimmunity for the lifespan of the mice (Kim et al. 2007).
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