A transgenic mouse strain with antigen-specific T cells (RAG1KO/sf/OVA) demonstrates that the scurfy (sf) mutation...

The scurfy (sf) murine mutation causes severe lymphoproliferation, which results in death of hemizygous males (sf/Y) by 22 to 26 days of age. The CD4+ T cells are crucial mediators of this disease. Recent publications have not only identified this mutation as the genetic equivalent of the human disease X-linked neonatal diabetes mellitus, enteropathy, and endocrinopathy syndrome, but also have indicated that the defective protein-scurfin-is a new forkhead/winged-helix protein with a frameshift mutation, resulting in a product without the functional forkhead. These results have lead to speculation that the scurfy gene acts by disrupting the T-cell tolerance mechanism, resulting in hyperresponsiveness and lack of down-regulation. The Rag1KO/sf/Y OVA strain, with virtually 100% of its CD4+ T cells reactive strictly to ovalbumin (OVA) peptide 323-339, is an excellent model for determination of the sf mutation's ability to disrupt tolerance. We hypothesized that Rag1KO/sf/OVA mice would not be tolerant to antigen at a dose that tolerizes control animals. We found that splenic cells from Rag1KO/sf/Y OVA mice injected with the same dose of OVA peptide that induces tolerance in cells from control mice proliferate in vitro in response to OVA peptide. These results are consistent with a defect in the pathway responsible for peripheral T-cell tolerization.