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.


CONCLUSIONS
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.
Lin
Wen
W
Division of Immunology, Allergy and Rheumatology, Department of Pediatrics, The David Geffen School of Medicine at the University of California at Los Angeles, MDCC 12-430, 10833 Le Conte Ave, Los Angeles, CA 90095-1752, USA.
Truong
Nga
N
Grossman
William J
WJ
Haribhai
Dipica
D
Williams
Calvin B
CB
Wang
Jiafang
J
Martín
Martín G
MG
Chatila
Talal A
TA
D000818:Animals; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006942:Hypergammaglobulinemia / Q000097:blood* / Q000235:genetics*; D006967:Hypersensitivity / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007073:Immunoglobulin E / Q000097:blood*; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012137:Respiratory System / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050800:STAT6 Transcription Factor; D007073:Immunoglobulin E