In vivo CpG DNA/toll-like receptor 9 interaction induces regulatory properties in CD4+CD62L+ T cells which prevent intestinal inflammation in the SCID transfer model of colitis.
METHODS
Cytosin-guanosin dinucleotide (CpG) motifs of bacterial DNA are known to be potent activators of innate immunity. We have shown previously that administration of CpG containing oligodeoxynucleotide (CpG-ODN) to mice before the onset of dextran sodium sulphate induced colitis ameliorated colitis and inhibited induction of proinflammatory cytokines. To investigate the possible involvement of CD4(+) T cells in the prophylactic CpG-ODN effects, we used the SCID transfer model of colitis.


RESULTS
CD4(+)CD62L(+) T cells from CpG-ODN treated donors did not induce significant intestinal inflammation in SCID recipients, in contrast with control cells. Additionally, cotransfer of these cells with CD4(+)CD62L(+) cells from normal mice protected recipient animals from colitis, indicating regulatory activity. Also, CD4(+)CD62L(+) cells from toll-like receptor 9 deficient animals induced a significantly more severe colitis in SCID recipients than cells from wild-type littermate controls, suggesting a similar protective role of "endogenous" bacterial DNA leading to a less "aggressive" phenotype of these cells. There was no detectable difference in regulatory T cell surface markers between aggressive and attenuated cell pools but attenuated cell pools showed reduced proliferation in vitro and in vivo and produced less interferon gamma, interleukin (IL)-5, and IL-6 after anti-CD3 stimulation.


CONCLUSIONS
Collectively, our data support the concept that both endogenous bacterial DNA and exogenously supplied CpG motifs of bacterial DNA induce regulatory properties in CD4(+) T cells. Therefore, bacterial DNA derived from the normal gut flora may contribute essentially to the homeostasis between effector and regulatory immune mechanisms in healthy individuals to protect them from chronic intestinal inflammation.
Obermeier
F
F
Department of Internal Medicine I, University of Regensburg, Germany. Florian.Obermeier@klinik.uni-regensburg.de
Strauch
U G
UG
Dunger
N
N
Grunwald
N
N
Rath
H C
HC
Herfarth
H
H
Schölmerich
J
J
Falk
W
W
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D020862:GC Rich Sequence / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D019041:L-Selectin / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008643:Mesentery / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009841:Oligonucleotides / Q000276:immunology*; D012007:Rectum / Q000276:immunology; D015431:Weight Loss / Q000502:physiology
D007378:Interleukins; D009841:Oligonucleotides; D019041:L-Selectin; D007371:Interferon-gamma