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)-β, as treatment with anti–IL-10R but not anti–TGF-β 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-γ 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.