B6.Cg-Foxp3^sf/J

Stock number: 004088
Product name: B6-scurfy
Research areas: Cell Biology Research, Dermatology Research, Developmental Biology Research, Endocrine Deficiency Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Mouse/Human Gene Homologs, Reproductive Biology Research

Description

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.

Detailed description

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. Foxp3^sf/Y males generally die by 16-25 days of age. Transgenic expression of Foxp3 prevents scurfy disease in Foxp3^sf/Y mice.

Neonatal thymectomy of scurfy males ameliorates disease and increases lifespan; athymic nude (Foxn1^nu/Foxn1^nu) Foxp3^sf/Y mice do not develop scurfy. While Cd4⁺ peripheral T cells from scurfy mice can transfer the scurfy disease phenotype to wild type, histocompatible Foxn1^nu/Foxn1^nu or Prkdc^scid/Prkdc^scid 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; Foxp3^sf/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. Foxp3^sf homozygous females can not be generated through traditional breeding because carrier males die by 25 days of age. By breeding nude Foxp3^sf/Y males with Foxp3^sf/+ females, however, homozygous scurfy females can be generated that are heterozygous for the recessive Foxn1^nu mutation. These homozygous scurfy females develop the same disease phenotype seen in hemizygous males, but they have a normal reproductive tract.

Development

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 Tyr^ch/p Tyr^c 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 Foxp3^sf/+ 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

Symbol: Foxp3^sf
Name: scurfy
MGI accession ID: MGI:1857034
Generation method: Spontaneous
Synonyms: Scurfy; sf
Marker symbol: Foxp3
Marker name: forkhead box P3
Marker synonyms: AIID; DIETER; IPEX; JM2; PIDX; RGD1562112; scurfin; XPID
Chromosome: X
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.