Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4.
Oral intake of protein leads to tolerance through the induction of regulatory T cells (Tr cells) in mesenteric lymph nodes (MLNs). Here we show that the inhibition of cyclooxygenase-2 (COX-2) in vivo suppressed oral tolerance and was associated with enhanced differentiation of interleukin (IL)-4-producing T cells and reduced Foxp3(+) Tr-cell differentiation in MLN. As a result, the functional suppressive capacity of these differentiated mucosal T cells was lost. IL-4 was causally related to loss of tolerance as treatment of mice with anti-IL-4 antibodies during COX-2 inhibition restored tolerance. Dendritic cells (DCs) in the MLN differentially expressed COX-2 and reductionist experiments revealed that selective inhibition of the enzyme in these cells inhibited Foxp3(+) Tr-cell differentiation in vitro. Importantly, the inhibition of COX-2 in MLN-DC caused increased GATA-3 expression and enhanced IL-4 release by T cells, which was directly related to impaired Tr-cell differentiation. These data provide crucial insights into the mechanisms driving de novo Tr-cell induction and tolerance in the intestine.
Broere
F
F
Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands.
du Pré
M F
MF
van Berkel
L A
LA
Garssen
J
J
Schmidt-Weber
C B
CB
Lambrecht
B N
BN
Hendriks
R W
RW
Nieuwenhuis
E E S
EE
Kraal
G
G
Samsom
J N
JN
D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000276:immunology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009578:Nitrobenzenes / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015847:Interleukin-4; D016718:Arachidonic Acid; D010047:Ovalbumin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2