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.
