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Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis.

Kullberg MC, Jankovic D, Gorelick PL, Caspar P, Letterio JJ, Cheever AW, Sher A - J. Exp. Med. (2002)

Bottom Line: 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.The induction of such cells in response to gut flora may be a mechanism protecting normal individuals against inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: 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

ABSTRACT
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.

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T cell–derived IL-10 mediates the disease-protective effect of WT CD45RBlow CD4+ cells. (A) Infected RAG/IL-10 double deficient mice were given either no cells or infected IL-10 KO CD4+ cells and infected WT CD4+ CD45RBlow cells as indicated (4 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Bars represent mean cecal histology scores ± SD of three mice per group. (B) Infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO, WT, and IL-4 KO mice as indicated (3 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean cecal histology scores ± SD of three mice per group from one representative experiment out of two performed. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving infected IL-10 KO cells alone.
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fig6: T cell–derived IL-10 mediates the disease-protective effect of WT CD45RBlow CD4+ cells. (A) Infected RAG/IL-10 double deficient mice were given either no cells or infected IL-10 KO CD4+ cells and infected WT CD4+ CD45RBlow cells as indicated (4 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Bars represent mean cecal histology scores ± SD of three mice per group. (B) Infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO, WT, and IL-4 KO mice as indicated (3 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean cecal histology scores ± SD of three mice per group from one representative experiment out of two performed. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving infected IL-10 KO cells alone.

Mentions: The possibility still existed that IL-10 derived from host non-T cells plays a role in disease protection mediated by infected WT cells in our model. Therefore, we performed cell transfers into double RAG/IL-10 KO mice. As demonstrated in single RAG KO recipients (Fig. 2 A), CD4+ cells from infected but not naive WT mice protected from colitis induced by IL-10 KO CD4+ cells plus H. hepaticus infection also in these IL-10–deficient RAG KO mice (unpublished data). This finding was supported by subsequent cell sorting experiments demonstrating that the disease-protective cells are found within the CD45RBlow CD4+ population and that their inhibitory effect is abrogated by treatment of the RAG/IL-10 KO recipients with anti–IL-10R mAb (Fig. 6 A).


Bacteria-triggered CD4(+) T regulatory cells suppress Helicobacter hepaticus-induced colitis.

Kullberg MC, Jankovic D, Gorelick PL, Caspar P, Letterio JJ, Cheever AW, Sher A - J. Exp. Med. (2002)

T cell–derived IL-10 mediates the disease-protective effect of WT CD45RBlow CD4+ cells. (A) Infected RAG/IL-10 double deficient mice were given either no cells or infected IL-10 KO CD4+ cells and infected WT CD4+ CD45RBlow cells as indicated (4 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Bars represent mean cecal histology scores ± SD of three mice per group. (B) Infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO, WT, and IL-4 KO mice as indicated (3 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean cecal histology scores ± SD of three mice per group from one representative experiment out of two performed. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving infected IL-10 KO cells alone.
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Related In: Results  -  Collection

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fig6: T cell–derived IL-10 mediates the disease-protective effect of WT CD45RBlow CD4+ cells. (A) Infected RAG/IL-10 double deficient mice were given either no cells or infected IL-10 KO CD4+ cells and infected WT CD4+ CD45RBlow cells as indicated (4 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Bars represent mean cecal histology scores ± SD of three mice per group. (B) Infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO, WT, and IL-4 KO mice as indicated (3 × 105 of each population) and then treated with control mAb or anti–IL-10R mAb for 4 wk. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean cecal histology scores ± SD of three mice per group from one representative experiment out of two performed. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving infected IL-10 KO cells alone.
Mentions: The possibility still existed that IL-10 derived from host non-T cells plays a role in disease protection mediated by infected WT cells in our model. Therefore, we performed cell transfers into double RAG/IL-10 KO mice. As demonstrated in single RAG KO recipients (Fig. 2 A), CD4+ cells from infected but not naive WT mice protected from colitis induced by IL-10 KO CD4+ cells plus H. hepaticus infection also in these IL-10–deficient RAG KO mice (unpublished data). This finding was supported by subsequent cell sorting experiments demonstrating that the disease-protective cells are found within the CD45RBlow CD4+ population and that their inhibitory effect is abrogated by treatment of the RAG/IL-10 KO recipients with anti–IL-10R mAb (Fig. 6 A).

Bottom Line: 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.The induction of such cells in response to gut flora may be a mechanism protecting normal individuals against inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: 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

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus