The functional insufficiency of human CD4+CD25 high T-regulatory cells in allergic asthma is subjected to TNF-alpha modulation.
BACKGROUND
Natural CD4(+)CD25(high)Foxp3(+) regulatory T (nTreg) cells are important in maintaining immunologic tolerance, but their role in the pathogenesis of allergic asthma is unclear. We studied the function of nTreg cells in allergic asthmatic children and assessed the factors which may relate to the functional insufficiency of nTreg cells.


METHODS
The percentage of CD4(+)CD25(high) Treg cells, the expression of Foxp3, and the cell-induced suppressive activity of nTreg cells isolated from nonatopic controls, allergic asthmatics, and allergen-specific immunotherapy (AIT)-treated asthmatic patients were studied.


RESULTS
Although the percentage of nTreg in peripheral blood mononuclear cells was increased, the expression of Foxp3 and its cell-induced suppressive activity were significantly lower in Dermatophagoides pteronyssinus (Der p)-sensitive asthmatic children when compared to nonatopic controls. In contrast, the expression of Foxp3 and the functional activity of nTreg cells were reversed in allergic asthmatics who received AIT. The addition of recombinant tumor necrosis factor (TNF)-alpha directly downregulated Foxp3 expression and abrogated the cell-induced suppressive function of Treg cells. The anti-TNF-alpha reagent, etanercept, restored the functional activity and Foxp3 expression of CD4(+)CD25(high) Treg derived from allergic asthmatics.


CONCLUSIONS
The functional insufficiency of nTreg cells in patients with allergic asthma may be related to the enhanced production of TNF-alpha and its effect on the Foxp3 expression. These results may explain, in part, the effectiveness of anti-TNF-alpha therapy in the treatment of allergic asthma.
Lin
Y-L
YL
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan.
Shieh
C-C
CC
Wang
J-Y
JY
D001249:Asthma / Q000235:genetics / Q000276:immunology*; D051927:CD24 Antigen / Q000235:genetics / Q000276:immunology*; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D011336:Probability; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
D051927:CD24 Antigen; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D014409:Tumor Necrosis Factor-alpha