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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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CD45RBlow CD4+ cells from naive WT mice are unable to protect RAG KO recipients from colitis induced by pathogenic T cells plus H. hepaticus infection. (A) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD45RBlow CD4+ cells from naive or infected WT mice (4 × 105 of each population), and tissues were analyzed 4 wk later. Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three mice per group. (B and C) Uninfected or H. hepaticus–infected (Hh-inf.) RAG KO mice were given either no cells or CD45RBhi CD4+ cells from naive WT mice and CD45RBlow CD4+ cells from naive or infected WT mice (3 × 105 of each population). Body weights were measured weekly and tissues were analyzed after 4 and 7.5 wk for infected and uninfected recipients, respectively. (B) Results shown represent mean body weights (expressed as a percentage of the weight 2 d after cell transfer) of four mice per group from the uninfected RAG KO recipients. No difference in body weight was observed between the four groups of infected recipients over the 4-wk time period that these groups were being followed (not depicted). (C) Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three or four mice per group. Statistical significance was tested for groups receiving pathogenic cells. *, P < 0.05 compared with mice receiving infected IL-10 KO CD4+ cells alone (A) or naive WT CD45RBhi CD4+ cells alone (C).
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fig7: CD45RBlow CD4+ cells from naive WT mice are unable to protect RAG KO recipients from colitis induced by pathogenic T cells plus H. hepaticus infection. (A) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD45RBlow CD4+ cells from naive or infected WT mice (4 × 105 of each population), and tissues were analyzed 4 wk later. Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three mice per group. (B and C) Uninfected or H. hepaticus–infected (Hh-inf.) RAG KO mice were given either no cells or CD45RBhi CD4+ cells from naive WT mice and CD45RBlow CD4+ cells from naive or infected WT mice (3 × 105 of each population). Body weights were measured weekly and tissues were analyzed after 4 and 7.5 wk for infected and uninfected recipients, respectively. (B) Results shown represent mean body weights (expressed as a percentage of the weight 2 d after cell transfer) of four mice per group from the uninfected RAG KO recipients. No difference in body weight was observed between the four groups of infected recipients over the 4-wk time period that these groups were being followed (not depicted). (C) Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three or four mice per group. Statistical significance was tested for groups receiving pathogenic cells. *, P < 0.05 compared with mice receiving infected IL-10 KO CD4+ cells alone (A) or naive WT CD45RBhi CD4+ cells alone (C).

Mentions: Our results clearly show that CD4+ cells must be obtained from H. hepaticus–infected IL-10–competent mice to confer protection from colitis triggered by this bacterium. These data could imply that the infection per se results in a selective expansion of a particular Treg population (for example, CD45RBlow cells) and/or that the disease-protective cells specifically recognize and respond to Helicobacter Ag. To examine the first possibility, MLN CD4+ cells from naive and infected WT mice were analyzed for their CD45RB and CD25 expression. In multiple experiments using mice at various time points after infection, no difference was observed in CD45RB and CD25 expression of MLN CD4+ cells between naive and H. hepaticus–infected animals (unpublished data). In addition, CD45RBlow CD4+ cells from uninfected WT mice were unable to prevent intestinal inflammation in infected RAG KO mice reconstituted with IL-10 KO cells (Fig. 7 A). Similarly, CD25+ CD4+ cells from infected but not naive WT animals inhibited disease (unpublished data).


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)

CD45RBlow CD4+ cells from naive WT mice are unable to protect RAG KO recipients from colitis induced by pathogenic T cells plus H. hepaticus infection. (A) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD45RBlow CD4+ cells from naive or infected WT mice (4 × 105 of each population), and tissues were analyzed 4 wk later. Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three mice per group. (B and C) Uninfected or H. hepaticus–infected (Hh-inf.) RAG KO mice were given either no cells or CD45RBhi CD4+ cells from naive WT mice and CD45RBlow CD4+ cells from naive or infected WT mice (3 × 105 of each population). Body weights were measured weekly and tissues were analyzed after 4 and 7.5 wk for infected and uninfected recipients, respectively. (B) Results shown represent mean body weights (expressed as a percentage of the weight 2 d after cell transfer) of four mice per group from the uninfected RAG KO recipients. No difference in body weight was observed between the four groups of infected recipients over the 4-wk time period that these groups were being followed (not depicted). (C) Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three or four mice per group. Statistical significance was tested for groups receiving pathogenic cells. *, P < 0.05 compared with mice receiving infected IL-10 KO CD4+ cells alone (A) or naive WT CD45RBhi CD4+ cells alone (C).
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fig7: CD45RBlow CD4+ cells from naive WT mice are unable to protect RAG KO recipients from colitis induced by pathogenic T cells plus H. hepaticus infection. (A) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD45RBlow CD4+ cells from naive or infected WT mice (4 × 105 of each population), and tissues were analyzed 4 wk later. Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three mice per group. (B and C) Uninfected or H. hepaticus–infected (Hh-inf.) RAG KO mice were given either no cells or CD45RBhi CD4+ cells from naive WT mice and CD45RBlow CD4+ cells from naive or infected WT mice (3 × 105 of each population). Body weights were measured weekly and tissues were analyzed after 4 and 7.5 wk for infected and uninfected recipients, respectively. (B) Results shown represent mean body weights (expressed as a percentage of the weight 2 d after cell transfer) of four mice per group from the uninfected RAG KO recipients. No difference in body weight was observed between the four groups of infected recipients over the 4-wk time period that these groups were being followed (not depicted). (C) Bars represent mean cecal (solid bars) and colonic (gray bars) histology scores ± SD of three or four mice per group. Statistical significance was tested for groups receiving pathogenic cells. *, P < 0.05 compared with mice receiving infected IL-10 KO CD4+ cells alone (A) or naive WT CD45RBhi CD4+ cells alone (C).
Mentions: Our results clearly show that CD4+ cells must be obtained from H. hepaticus–infected IL-10–competent mice to confer protection from colitis triggered by this bacterium. These data could imply that the infection per se results in a selective expansion of a particular Treg population (for example, CD45RBlow cells) and/or that the disease-protective cells specifically recognize and respond to Helicobacter Ag. To examine the first possibility, MLN CD4+ cells from naive and infected WT mice were analyzed for their CD45RB and CD25 expression. In multiple experiments using mice at various time points after infection, no difference was observed in CD45RB and CD25 expression of MLN CD4+ cells between naive and H. hepaticus–infected animals (unpublished data). In addition, CD45RBlow CD4+ cells from uninfected WT mice were unable to prevent intestinal inflammation in infected RAG KO mice reconstituted with IL-10 KO cells (Fig. 7 A). Similarly, CD25+ CD4+ cells from infected but not naive WT animals inhibited disease (unpublished data).

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