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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


Background and 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 γ, 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.

  • IBD, inflammatory bowel disease
  • CpG, cytosin-guanosin dinucleotide
  • CpG-ODN, CpG containing oligodeoxynucleotide
  • TLR, toll-like receptor
  • IL, interleukin
  • TNF, tumour necrosis factor
  • IFN-γ, interferon γ
  • TGF-β, transforming growth factor β
  • PBS, phosphate buffered saline
  • RT-PCR, reverse transcription-polymerase chain reaction
  • experimental colitis
  • CpG motifs
  • bacterial DNA
  • SCID transfer model of colitis

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