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

• Published in: Gut Vol. 54; no. 10; pp. 1428 - 1436
• Main Authors: Obermeier, F, Strauch, U G, Dunger, N, Grunwald, N, Rath, H C, Herfarth, H, Schölmerich, J, Falk, W
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and British Society of Gastroenterology 01.10.2005; BMJ; BMJ Publishing Group LTD; Copyright 2005 by Gut
• Subjects: Animals; bacterial DNA; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Colitis - immunology; Colitis - metabolism; CpG; CpG containing oligodeoxynucleotide; CpG motifs; CpG-ODN; Cytokines; cytosin-guanosin dinucleotide; Deoxyribonucleic acid; Disease Models, Animal; DNA; experimental colitis; Experiments; GC Rich Sequence - immunology; IBD; IFN-γ; Immune system; Immunomodulators; Inflammation; Inflammatory Bowel Disease; interferon γ; Interferon-gamma - immunology; interleukin; Interleukins - immunology; Intestinal Mucosa - immunology; L-Selectin - immunology; Lymph Nodes - immunology; Lymphocytes; Medical sciences; Mesentery - immunology; Mice; Mice, Inbred BALB C; Mice, SCID; Oligonucleotides - immunology; PBS; Pharmacology. Drug treatments; phosphate buffered saline; Rectum - immunology; reverse transcription-polymerase chain reaction; Rodents; RT-PCR; SCID transfer model of colitis; TGF-β; TLR; TNF; toll-like receptor; transforming growth factor β; Tumor necrosis factor-TNF; tumour necrosis factor; Weight Loss - physiology; Germany; Cytokine; Inflammation; Monoclonal antibody; Dextran; Immunomodulator; Prevention; In vivo; Muromonab-CD3; Chronic; Immunological investigation; Blood substitute; DNA; Anticytokine; T-Lymphocyte; Digestive diseases; Intestinal disease; Interferon; Models; Colitis; Immunosuppressive agent
• ISSN: 0017-5749; 1468-3288; 1458-3288
• DOI: 10.1136/gut.2004.046946

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.