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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 H. hepaticus–infected WT mice protect RAG KO animals from colitis induced by IL-10 KO CD4+ cells plus bacterial infection. (A) H. hepaticus–infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO mice and CD4+ cells from naive or infected WT mice as indicated (4 × 105 of each population). Intestinal pathology was analyzed 4 wk later. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean histology scores ± SD of three mice per group except for groups receiving WT cells alone, in which case, due to limited cell numbers, only two mice per group were used. Similar results were seen in ascending colon (although histology scores were lower) and when disease was induced by the transfer of CD4+ cells from naive IL-10 KO mice (not depicted). (B) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD4+, CD45RBhi CD4+, or CD45RBlow CD4+ cells from infected WT mice as indicated (4 × 105 of each population). Pathology in the cecum (solid bars) and ascending colon (gray bars) were analyzed 4 wk later. Bars represent mean histology scores ± SD of six or seven mice per group pooled from two separate experiments except for the group receiving IL-10 KO CD4+ cells plus infected WT CD4+ cells (n = 3), which was included in only one of the experiments. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving IL-10 KO cells alone.
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fig2: CD45RBlow CD4+ cells from H. hepaticus–infected WT mice protect RAG KO animals from colitis induced by IL-10 KO CD4+ cells plus bacterial infection. (A) H. hepaticus–infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO mice and CD4+ cells from naive or infected WT mice as indicated (4 × 105 of each population). Intestinal pathology was analyzed 4 wk later. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean histology scores ± SD of three mice per group except for groups receiving WT cells alone, in which case, due to limited cell numbers, only two mice per group were used. Similar results were seen in ascending colon (although histology scores were lower) and when disease was induced by the transfer of CD4+ cells from naive IL-10 KO mice (not depicted). (B) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD4+, CD45RBhi CD4+, or CD45RBlow CD4+ cells from infected WT mice as indicated (4 × 105 of each population). Pathology in the cecum (solid bars) and ascending colon (gray bars) were analyzed 4 wk later. Bars represent mean histology scores ± SD of six or seven mice per group pooled from two separate experiments except for the group receiving IL-10 KO CD4+ cells plus infected WT CD4+ cells (n = 3), which was included in only one of the experiments. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving IL-10 KO cells alone.

Mentions: Next, we investigated whether we could protect the IL-10 KO T cell reconstituted, infected RAG KO mice from disease by cotransfer of WT cells. As shown in Fig. 2 A, whereas infected RAG KO hosts receiving IL-10 KO CD4+ cells alone developed colitis, animals receiving a 1:1 mixture of MLN CD4+ cells from IL-10 KO and infected WT mice did not develop intestinal inflammation. If the WT CD4+ cells originated from uninfected (naive) WT mice, however, no protection was observed (Fig. 2 A). In fact, the transfer of naive WT CD4+ cells alone induced colitis in the infected T cell–deficient mice, whereas CD4+ cells obtained from infected WT animals did not induce disease in these recipients. Whereas minimal inflammation was observed in infected T cell–deficient mice with no cell transfer (Fig. 3 A), infected RAG KO recipients of IL-10 KO CD4+ lymphocytes displayed large numbers of cells infiltrating the intestine (Fig. 3 B). Co-transfer of infected but not naive WT CD4+ cells blocked the accumulation of these inflammatory infiltrates (Fig. 3, C and D).


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 H. hepaticus–infected WT mice protect RAG KO animals from colitis induced by IL-10 KO CD4+ cells plus bacterial infection. (A) H. hepaticus–infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO mice and CD4+ cells from naive or infected WT mice as indicated (4 × 105 of each population). Intestinal pathology was analyzed 4 wk later. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean histology scores ± SD of three mice per group except for groups receiving WT cells alone, in which case, due to limited cell numbers, only two mice per group were used. Similar results were seen in ascending colon (although histology scores were lower) and when disease was induced by the transfer of CD4+ cells from naive IL-10 KO mice (not depicted). (B) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD4+, CD45RBhi CD4+, or CD45RBlow CD4+ cells from infected WT mice as indicated (4 × 105 of each population). Pathology in the cecum (solid bars) and ascending colon (gray bars) were analyzed 4 wk later. Bars represent mean histology scores ± SD of six or seven mice per group pooled from two separate experiments except for the group receiving IL-10 KO CD4+ cells plus infected WT CD4+ cells (n = 3), which was included in only one of the experiments. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving IL-10 KO cells alone.
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fig2: CD45RBlow CD4+ cells from H. hepaticus–infected WT mice protect RAG KO animals from colitis induced by IL-10 KO CD4+ cells plus bacterial infection. (A) H. hepaticus–infected RAG KO mice (solid bars) were inoculated with CD4+ cells from infected IL-10 KO mice and CD4+ cells from naive or infected WT mice as indicated (4 × 105 of each population). Intestinal pathology was analyzed 4 wk later. Naive (open bar) and infected RAG KO animals receiving no cells were included as controls. Bars represent mean histology scores ± SD of three mice per group except for groups receiving WT cells alone, in which case, due to limited cell numbers, only two mice per group were used. Similar results were seen in ascending colon (although histology scores were lower) and when disease was induced by the transfer of CD4+ cells from naive IL-10 KO mice (not depicted). (B) Infected RAG KO mice were given either no cells or CD4+ cells from infected IL-10 KO mice and CD4+, CD45RBhi CD4+, or CD45RBlow CD4+ cells from infected WT mice as indicated (4 × 105 of each population). Pathology in the cecum (solid bars) and ascending colon (gray bars) were analyzed 4 wk later. Bars represent mean histology scores ± SD of six or seven mice per group pooled from two separate experiments except for the group receiving IL-10 KO CD4+ cells plus infected WT CD4+ cells (n = 3), which was included in only one of the experiments. Statistical significance was tested for groups receiving IL-10 KO cells. *, P < 0.05 compared with mice receiving IL-10 KO cells alone.
Mentions: Next, we investigated whether we could protect the IL-10 KO T cell reconstituted, infected RAG KO mice from disease by cotransfer of WT cells. As shown in Fig. 2 A, whereas infected RAG KO hosts receiving IL-10 KO CD4+ cells alone developed colitis, animals receiving a 1:1 mixture of MLN CD4+ cells from IL-10 KO and infected WT mice did not develop intestinal inflammation. If the WT CD4+ cells originated from uninfected (naive) WT mice, however, no protection was observed (Fig. 2 A). In fact, the transfer of naive WT CD4+ cells alone induced colitis in the infected T cell–deficient mice, whereas CD4+ cells obtained from infected WT animals did not induce disease in these recipients. Whereas minimal inflammation was observed in infected T cell–deficient mice with no cell transfer (Fig. 3 A), infected RAG KO recipients of IL-10 KO CD4+ lymphocytes displayed large numbers of cells infiltrating the intestine (Fig. 3 B). Co-transfer of infected but not naive WT CD4+ cells blocked the accumulation of these inflammatory infiltrates (Fig. 3, C and D).

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