Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma.
BACKGROUND
T regulatory (T reg ) cells are characterized by expression of suppressive cytokines and the transcription factor FOXP3. They play a key role in balancing immune responses and maintain peripheral tolerance against antigens and allergens. The loss of peripheral tolerance against allergens causes diseases that can be therapeutically controlled with glucocorticoids.


OBJECTIVE
The present study investigates whether glucocorticoids affect the activity of T reg cells on the basis of FOXP3 and cytokine expression.


METHODS
CD4 + T cells from healthy donors and glucocorticoid-treated asthmatic patients were isolated, and expression of FOXP3, along with IL-10 and TGF-beta1, was determined. The effect of glucocorticoids on T reg cells was measured in vivo before and after GC treatment and in in vitro cultures.


RESULTS
FOXP3 mRNA expression was significantly increased in asthmatic patients receiving inhaled glucocorticoid treatment, systemic glucocorticoid treatment, or both. FOXP3 tightly correlated with IL10 mRNA expression. No correlation of FOXP3 mRNA expression was observed in relation to a (GT)n microsatellite promoter polymorphism on chromosome Xp11.23 or total IgE level. The frequency of CD25 + memory CD4 + T cells and transient FOXP3 mRNA expression by CD4 + T cells significantly increased after systemic glucocorticoid treatment, whereas TGFB1 expression did not change. Furthermore, glucocorticoids induced IL10 and FOXP3 expression in short-term and long-term cultures in vitro.


CONCLUSIONS
These findings demonstrate that glucocorticoid treatment is not only immunosuppressive and anti-inflammatory but also promotes or initiates differentiation toward T R 1 cells by a FOXP3-dependent mechanism. Strategies that convert transient glucocorticoid-induced T reg activity into a stable phenotype might improve allergy and asthma therapy.
Karagiannidis
Christian
C
Swiss Institute of Allergy and Asthma Research, Davos, Switzerland.
Akdis
Mübeccel
M
Holopainen
Päivi
P
Woolley
Niina J
NJ
Hense
Gabriele
G
Rückert
Beate
B
Mantel
Pierre-Yves
PY
Menz
Günther
G
Akdis
Cezmi A
CA
Blaser
Kurt
K
Schmidt-Weber
Carsten B
CB
D000328:Adult; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D016753:Interleukin-10 / Q000235:genetics; D018895:Microsatellite Repeats; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D007073:Immunoglobulin E