Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis.
We have previously demonstrated that interleukin (IL)-10-deficient (IL-10 knockout [KO]) but not wild-type (WT) mice develop colitis after infection with Helicobacter hepaticus. Here, we show that infected recombination activating gene (RAG) KO mice develop intestinal inflammation after reconstitution with CD4(+) T cells from IL-10 KO animals and that the cotransfer of CD4(+) T cells from H. hepaticus-infected but not uninfected WT mice prevents this colitis. The disease-protective WT CD4(+) cells are contained within the CD45RB(low) fraction and unexpectedly were found in both the CD25(+) and the CD25(-) subpopulations of these cells, their frequency being higher in the latter. The mechanism by which CD25(+) and CD25(-) CD45RB(low) CD4(+) cells block colitis involves IL-10 and not transforming growth factor (TGF)-beta, as treatment with anti-IL-10R but not anti-TGF-beta monoclonal antibody abrogated their protective effect. In vitro, CD45RB(low) CD4(+) cells from infected WT mice were shown to produce IL-10 and suppress interferon-gamma production by IL-10 KO CD4(+) cells in an H. hepaticus antigen-specific manner. Together, our data support the concept that H. hepaticus infection results in the induction in WT mice of regulatory T cells that prevent bacteria-induced colitis. The induction of such cells in response to gut flora may be a mechanism protecting normal individuals against inflammatory bowel disease.
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases/NIH, Building 50, Room 6146, 50 South Drive, Bethesda, MD 20892, USA. MKullberg@niaid.nih.gov
Marika C
MC
Kullberg
Dragana
D
Jankovic
Peter L
PL
Gorelick
Patricia
P
Caspar
John J
JJ
Letterio
Allen W
AW
Cheever
Alan
A
Sher
D019264:Adoptive Transfer; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003092:Colitis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D016998:Helicobacter / Q000276:immunology; D016481:Helicobacter Infections / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta / Q000276:immunology
D000942:Antigens, Bacterial; D015415:Biomarkers; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; C064655:V(D)J recombination activating protein 2; D016753:Interleukin-10; D015847:Interleukin-4; D017493:Leukocyte Common Antigens