Scurfy mice have defective T cell tolerance leading to an X-linked lymphoproliferative disease that parallels the X-linked autoimmunity-allergic disregulation syndrome (XLAAD) in humans. Hemizygous males are characterized by runting, scaly, crusty skin on the eyelids, ears and tails, dermal thickening, squinted eyes, cachexia, reddening and swelling of the genital papilla, and small testicles that are retained in the abdominal cavity. Homozygous scurfy females develop the same disease phenotype seen in hemizygous males, but they have a normal reproductive tract.
Scurfy mice develop an X-linked lymphoproliferative disease resulting from defective T cell tolerance. Phenotypes associated with these mice include runting, scaly, crusty skin on the eyelids, ears and tails, dermal thickening, squinted eyes, cachexia, reddening and swelling of the genital papilla, and small testicles that are retained in the abdominal cavity. This disorder, which parallels X-linked autoimmunity-allergic disregulation syndrome (XLAAD) in humans, results in Coombs' test-positive anemia, hypergammaglobulinemia, a small, thin thymus, and lymphohistiocytic proliferation in the skin and lymphoid organs, with splenomegaly, lymphadenomegaly, and hepatomegaly. Foxp3sf/Y males generally die by 16-25 days of age. Transgenic expression of Foxp3 prevents scurfy disease in Foxp3sf/Y mice.
Neonatal thymectomy of scurfy males ameliorates disease and increases lifespan; athymic nude (Foxn1nu/Foxn1nu) Foxp3sf/Y mice do not develop scurfy. While Cd4+ peripheral T cells from scurfy mice can transfer the scurfy disease phenotype to wild type, histocompatible Foxn1nu/Foxn1nu or Prkdcscid/Prkdcscid hosts, bone marrow transplantation from scurfy homozygotes fails to transfer disease. Also, neither neonatal inoculation with wild type bone marrow, nor thymic lobe transplants from wild type donors into carrier males prevents disease. Northern blot analysis of skin, lymph nodes and spleen revealed over-expression of Il2, Il4, Il5, Il10, Il6, IFNg, and TNFa; over-expression of these last three is especially high. Peripheral Cd4+ T cells from scurfy mice are hyper-responsive to antigen, have an activated phenotype (Cd44+, Cd69+, Cd25+, Cd80+, Cd86+), a decreased requirement for Cd28 co-stimulation, and a decreased sensitivity to tyrosine kinase inhibitors and cyclosporin A. Prenatal or neonatal injection with anti-Cd4 antibodies can delay the onset of disease, as can the targeted disruption of Cd4. Cd8+ cells do not transfer disease, and targeted disruption of B2m does not alter disease onset. Activation of peripheral T cells is necessary to initiate the scurfy pathology; Foxp3sf/Y mice carrying a transgene for an ovalbumin-specific TCR and a targeted mutation of Rag1 fail to develop the scurfy disease phenotype until challenged with ovalbumin. Foxp3sf homozygous females can not be generated through traditional breeding because carrier males die by 25 days of age. By breeding nude Foxp3sf/Y males with Foxp3sf/+ females, however, homozygous scurfy females can be generated that are heterozygous for the recessive Foxn1nu mutation. These homozygous scurfy females develop the same disease phenotype seen in hemizygous males, but they have a normal reproductive tract.
The scurfy mutation arose spontaneously at the Oak Ridge National Laboratory in 1949 in the partially inbred MR stock. This strain was a multiple recessive stock of seven mutations, primarily coat color mutations. Scurfy was maintained either by backcross onto 129/Rl-p Tyrch/p Tyrc or by breeding heterozygous females to (C3H/Rl x 101/Rl)F1 or (101/Rl x C3H/Rl)F1 males at each generation to keep it on a non-inbred background. Means et al. obtained scurfy mice from Yvonne Boyd at Harwell where they were maintained by breeding to (C3H/Rl x 101/Rl)F1. Means et al. backcrossed Foxp3sf/+ females to C57BL/6NTac males. In 2001 The Jackson Laboratory received N8 mice and backcrossed to C57BL/6J. (Russell et al., 1959; Godfrey et al., 1991; Means et al., 2000.)
|Allele Synonym(s)||Scurfy; sf|
|Gene Symbol and Name||Foxp3, forkhead box P3|
|Gene Synonym(s)||AIID; DIETER; IPEX; JM2; PIDX; RGD1562112; XPID; scurfin; scurfy; sf|
|Strain of Origin||STOCK MR|
|Molecular Note||Insertion of two adenosine residues into exon 8, resulting in a 2 bp shift in the reading frame. This allele is predicted to produce a truncated protein lacking the carboxy-terminal forkhead domain.|
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