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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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CD25− CD45RBlow as well as CD25+ CD45RBlow CD4+ cells from infected WT mice protect RAG KO mice against colitis. Infected RAG KO mice were given either no cells or 3 × 105 CD4+ cells from infected IL-10 KO mice either alone or with 3 × 105 CD45RBlow CD4+ cells, 3 × 105, 105, or 3.3 × 104 CD25− CD45RBlow, or CD25+ CD45RBlow CD4+ cells from infected WT mice as indicated. (A) Pathology in the cecum and (B) ascending colon was analyzed 4 wk later. •, an individual mouse; —, the average for each group. Data shown are pooled from two separate experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared with infected mice receiving IL-10 KO cells alone.
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fig4: CD25− CD45RBlow as well as CD25+ CD45RBlow CD4+ cells from infected WT mice protect RAG KO mice against colitis. Infected RAG KO mice were given either no cells or 3 × 105 CD4+ cells from infected IL-10 KO mice either alone or with 3 × 105 CD45RBlow CD4+ cells, 3 × 105, 105, or 3.3 × 104 CD25− CD45RBlow, or CD25+ CD45RBlow CD4+ cells from infected WT mice as indicated. (A) Pathology in the cecum and (B) ascending colon was analyzed 4 wk later. •, an individual mouse; —, the average for each group. Data shown are pooled from two separate experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared with infected mice receiving IL-10 KO cells alone.

Mentions: To further phenotype the disease-protective CD45RBlow CD4+ lymphocytes, we sorted CD25+ and CD25− cells from this population and asked whether these cells could inhibit colitis. Two recent reports have demonstrated that CD25+ CD45RBlow CD4+ cells from naive mice are superior to the CD25− subpopulation in blocking CD45RBhi-induced colitis in T cell–deficient mice (18, 19). Our experiments using IL-10 KO CD4+ cells plus H. hepaticus to induce disease indicate that the CD25+ and CD25− populations prevent disease to a similar degree when given at a 1:1 ratio with the pathogenic cells. However, at an IL-10 KO CD4+/WT CD45RBlow ratio of 3:1 or 9:1, the CD25− CD45RBlow cells are more effective in blocking intestinal inflammation than the CD25+ subpopulation (Fig. 4) . Thus, when given with 3 × 105 IL-10 KO CD4+ cells, 105 of the CD25− CD45RBlow WT cells were able to significantly suppress pathology in both the cecum and the colon, whereas the same number of cells of the CD25+ subpopulation conferred partial protection only in the cecum. Although disease protection by the CD25+ cells was completely lost at 3.3 × 104 cells, the CD25− cells still suppressed inflammation at this dosage (Fig. 4).


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)

CD25− CD45RBlow as well as CD25+ CD45RBlow CD4+ cells from infected WT mice protect RAG KO mice against colitis. Infected RAG KO mice were given either no cells or 3 × 105 CD4+ cells from infected IL-10 KO mice either alone or with 3 × 105 CD45RBlow CD4+ cells, 3 × 105, 105, or 3.3 × 104 CD25− CD45RBlow, or CD25+ CD45RBlow CD4+ cells from infected WT mice as indicated. (A) Pathology in the cecum and (B) ascending colon was analyzed 4 wk later. •, an individual mouse; —, the average for each group. Data shown are pooled from two separate experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared with infected mice receiving IL-10 KO cells alone.
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Related In: Results  -  Collection

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fig4: CD25− CD45RBlow as well as CD25+ CD45RBlow CD4+ cells from infected WT mice protect RAG KO mice against colitis. Infected RAG KO mice were given either no cells or 3 × 105 CD4+ cells from infected IL-10 KO mice either alone or with 3 × 105 CD45RBlow CD4+ cells, 3 × 105, 105, or 3.3 × 104 CD25− CD45RBlow, or CD25+ CD45RBlow CD4+ cells from infected WT mice as indicated. (A) Pathology in the cecum and (B) ascending colon was analyzed 4 wk later. •, an individual mouse; —, the average for each group. Data shown are pooled from two separate experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared with infected mice receiving IL-10 KO cells alone.
Mentions: To further phenotype the disease-protective CD45RBlow CD4+ lymphocytes, we sorted CD25+ and CD25− cells from this population and asked whether these cells could inhibit colitis. Two recent reports have demonstrated that CD25+ CD45RBlow CD4+ cells from naive mice are superior to the CD25− subpopulation in blocking CD45RBhi-induced colitis in T cell–deficient mice (18, 19). Our experiments using IL-10 KO CD4+ cells plus H. hepaticus to induce disease indicate that the CD25+ and CD25− populations prevent disease to a similar degree when given at a 1:1 ratio with the pathogenic cells. However, at an IL-10 KO CD4+/WT CD45RBlow ratio of 3:1 or 9:1, the CD25− CD45RBlow cells are more effective in blocking intestinal inflammation than the CD25+ subpopulation (Fig. 4) . Thus, when given with 3 × 105 IL-10 KO CD4+ cells, 105 of the CD25− CD45RBlow WT cells were able to significantly suppress pathology in both the cecum and the colon, whereas the same number of cells of the CD25+ subpopulation conferred partial protection only in the cecum. Although disease protection by the CD25+ cells was completely lost at 3.3 × 104 cells, the CD25− cells still suppressed inflammation at this dosage (Fig. 4).

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