The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published 19 August 2002. doi:10.1084/jem.20020556
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© Rockefeller University Press, 0022-1007/2002/8/505/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 4, August 19, 2002 505-515
Bacteria-triggered CD4+ T Regulatory Cells Suppress Helicobacter hepaticus–induced Colitis

Marika C. Kullberg1, Dragana Jankovic1, Peter L. Gorelick3, Patricia Caspar1, John J. Letterio2, Allen W. Cheever4 and Alan Sher1

1 Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID)
2 Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
3 Animal Health Diagnostic Laboratory, Laboratory Animal Sciences Program, NCI-Frederick, Science Applications International Corporation, Frederick, MD 21702
4 The Biomedical Research Institute, Rockville, MD 20852

Address correspondence to Marika C. Kullberg, Immunobiology Section, Laboratory of Parasitic Diseases, NIAID, NIH, Building 50, Room 6146, 50 South Drive, Bethesda, MD 20892. Phone: 301-594-3082; Fax: 301-402-0890; E-mail: MKullberg{at}niaid.nih.gov

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 CD45RBlow 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- CD45RBlow CD4+ cells block colitis involves IL-10 and not transforming growth factor (TGF)-ß, as treatment with anti–IL-10R but not anti–TGF-ß monoclonal antibody abrogated their protective effect. In vitro, CD45RBlow 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.

Key Words: inflammatory bowel disease • regulatory T cells • intestinal flora • CD25 • immunoregulation


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