Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope.
It is now well established that the intestinal flora plays an important role in the pathogenesis of inflammatory bowel disease (IBD). However, whether bacteria serve as the sole target of the immune response in this process or whether they act indirectly by triggering an anti-self response is still unclear. We have previously shown that specific pathogen-free IL-10-deficient (IL-10 KO) mice develop a T helper (Th1)-cytokine associated colitis after experimental infection with Helicobacter hepaticus. We here show that H. hepaticus Ag (SHelAg)-specific CD4+ Th1 clones transfer disease to H. hepaticus-infected T cell-deficient RAG KO hosts. Importantly, uninfected recipients of the SHelAg-specific clones did not develop intestinal inflammation, and a control Schistosoma mansoni-specific Th1 clone did not induce colitis upon transfer to infected RAG KO mice. The disease-inducing T cell clones recognized antigen(s) (Ag) specifically expressed by certain Helicobacter species as they responded when stimulated in vitro with H. hepaticus and Helicobacter typhlonius Ag, but not when cultured with Ag preparations from Helicobacter pylori, various non-helicobacter bacteria, or with cecal bacterial lysate from uninfected mice. Characterization of the Ag specificity of one of the clones showed that it reacts uniquely with a 15-mer peptide epitope on the flagellar hook protein (FlgE) of H. hepaticus presented by I-Ab. Together, our results demonstrate that colitis can be induced by clonal T cell populations that are highly specific for target Ag on intestinal bacteria, suggesting that an aberrant T cell response directed against gut flora is sufficient to trigger IBD.
Kullberg
Marika C
MC
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. mkullberg@niaid.nih.gov
Andersen
John F
JF
Gorelick
Peter L
PL
Caspar
Patricia
P
Suerbaum
Sebastian
S
Fox
James G
JG
Cheever
Allen W
AW
Jankovic
Dragana
D
Sher
Alan
A
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D002999:Clone Cells; D016207:Cytokines / Q000032:analysis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D016998:Helicobacter / Q000235:genetics / Q000276:immunology; D016481:Helicobacter Infections / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016415:Sequence Alignment
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D000939:Epitopes; C097681:FlgE protein, Bacteria; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D016753:Interleukin-10