Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice.
BACKGROUND: Regulatory T cells have been proposed to play an important role in regulating allergic inflammation. The transcription factor Foxp3 is a master switch gene that controls the development and function of natural and adaptive CD4(+)CD25(+) regulatory T (T(R)) cells. In human subjects loss-of-function Foxp3 mutations trigger lymphoproliferation, autoimmunity, and intense allergic inflammation in a disease termed immune dysregulation polyendocrinopathy enteropathy-X-linked syndrome. OBJECTIVE: We sought to examine the evolution and attributes of allergic inflammation in mice with a targeted loss-of-function mutation in the murine Foxp3 gene that recapitulates a known disease-causing human Foxp3 mutation. METHODS: Foxp3 mutant mice were generated by means of knock-in mutagenesis and were analyzed for histologic, immunologic, and hematologic abnormalities. The role of signal transducer and activator of transcription 6 (Stat6) in disease pathogenesis was analyzed by using Stat6 and Foxp3 double-mutant mice. RESULTS: Foxp3 mutant mice developed an intense multiorgan inflammatory response associated with allergic airway inflammation, a striking hyperimmunoglobulinemia E, eosinophilia, and dysregulated T(H)1 and T(H)2 cytokine production in the absence of overt T(H)2 skewing. Concurrent Stat6 deficiency reversed the hyperimmunoglobulinemia E and eosinophilia and delayed mortality, which is consistent with a pathogenic role for allergic inflammation in Foxp3 deficiency. CONCLUSION: Allergic dysregulation is a common and fundamental consequence of loss of CD4(+)CD25(+) T(R) cells caused by Foxp3 deficiency in different species. Abnormalities affecting T(R) cells might contribute to a variety of allergic diseases.[1]References
- Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. Lin, W., Truong, N., Grossman, W.J., Haribhai, D., Williams, C.B., Wang, J., Martín, M.G., Chatila, T.A. J. Allergy Clin. Immunol. (2005) [Pubmed]
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