Allergic dysregulation and hyperimmunoglobulinemia e in Foxp3 mutant mice

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Abstract

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 (TR) 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 TH1 and TH2 cytokine production in the absence of overt TH2 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+ TR cells caused by Foxp3 deficiency in different species. Abnormalities affecting TR cells might contribute to a variety of allergic diseases. © 2005 American Academy of Allergy, Asthma and Immunology.

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Lin, W., Truong, N., Grossman, W. J., Haribhai, D., Williams, C. B., Wang, J., … Chatila, T. A. (2005). Allergic dysregulation and hyperimmunoglobulinemia e in Foxp3 mutant mice. Journal of Allergy and Clinical Immunology, 116(5), 1106–1115. https://doi.org/10.1016/j.jaci.2005.08.046

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