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An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.

Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F - J. Exp. Med. (1999)

Bottom Line: The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody.Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population.These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom.

ABSTRACT
A T helper cell type 1-mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RB(high) CD4(+) T cells and can be prevented by cotransfer of the CD45RB(low) subset. The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population. This population isolated from IL-10-deficient (IL-10(-/-)) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti-murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RB(low) CD4(+) cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RB(high) CD4(+) cells, as CD45RB(low) CD4(+) cells from WT mice were able to inhibit colitis induced by IL-10(-/-) CD45RB(high) CD4(+) cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

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Representative photomicrographs of the descending colon of RAG-2−/− mice after transfer of subpopulations of CD4+ T cells from WT or IL-10−/− mice. (A) Severe colitis in a mouse injected with CD45RBhigh CD4+ T cells from WT mice. (B) Normal appearance of the colon in a mouse restored with WT CD45RBhigh and WT CD45RBlow CD4+ T cells, indicating that the WT CD45RBlow population is able to inhibit disease induced by WT CD45RBhigh CD4+ T cells. (C) Severe colitis in a mouse cotransferred with WT CD45RBhigh CD4+ T cells and IL-10−/− CD45RBlow CD4+ cells, indicating that the IL-10−/− CD45RBlow subpopulation is unable to protect from the disease. (D) Severe colitis in a mouse receiving only IL-10−/− CD45RBlow cells, indicating that this population is able to induce disease. Hematoxylin and eosin; original magnifications: ×50.
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Figure 1: Representative photomicrographs of the descending colon of RAG-2−/− mice after transfer of subpopulations of CD4+ T cells from WT or IL-10−/− mice. (A) Severe colitis in a mouse injected with CD45RBhigh CD4+ T cells from WT mice. (B) Normal appearance of the colon in a mouse restored with WT CD45RBhigh and WT CD45RBlow CD4+ T cells, indicating that the WT CD45RBlow population is able to inhibit disease induced by WT CD45RBhigh CD4+ T cells. (C) Severe colitis in a mouse cotransferred with WT CD45RBhigh CD4+ T cells and IL-10−/− CD45RBlow CD4+ cells, indicating that the IL-10−/− CD45RBlow subpopulation is unable to protect from the disease. (D) Severe colitis in a mouse receiving only IL-10−/− CD45RBlow cells, indicating that this population is able to induce disease. Hematoxylin and eosin; original magnifications: ×50.

Mentions: To determine whether the CD45RBlow CD4+ population from IL-10−/− mice contained regulatory T cells, this population was compared with CD45RBlow CD4+ cells from WT mice for the ability to inhibit colitis induced in RAG-2−/− mice by transfer of WT CD45RBhigh CD4+ cells. Expression of CD45RB was similar on CD4+ T cells from 10–12-wk-old IL-10−/− and WT mice (data not shown). WT CD45RBhigh CD4+ cells (4 × 105) were transferred to syngeneic RAG-2−/− mice either alone or in combination with 2 × 105 CD45RBlow CD4+ cells from WT or IL-10−/− mice. As controls, the CD45RBlow CD4+ populations from IL-10−/− or WT mice were transferred alone and some mice were not reconstituted. 10–12 wk after T cell reconstitution, mice were killed and the development of colonic inflammation was assessed. As described previously 34, transfer of CD45RBhigh CD4+ cells into RAG-2−/− mice resulted in the development of severe colitis (Fig. 1 A) in the majority of mice (63.4%; Table , top). This colitis was characterized by an extensive inflammatory cell infiltrate, marked epithelial cell hyperplasia, and depletion of mucin-secreting cells. Cotransfer of the CD45RBlow CD4+ population significantly inhibited (P < 0.005) the development of colitis, as the majority of mice in this group (83.8%; Table , top) had minimal changes in the intestine (Fig. 1 B). In contrast, cotransfer of CD45RBlow CD4+ cells from IL-10−/− mice failed to protect mice from colitis, as the majority of mice in this group (64.2%; Table , top) developed intestinal inflammation (Fig. 1 C) identical to that seen in mice restored with CD45RBhigh CD4+ cells alone. Not only did the CD45RBlow population from IL-10−/− mice fail to protect from colitis, this population actually induced disease with similar characteristics (Fig. 1 D) and incidence (59.0%; Table , top) to that induced by WT CD45RBhigh CD4+ cells. As described previously 4, immune-deficient mice either unreconstituted or restored with WT CD45RBlow CD4+ cells exhibited no pathological changes in the intestine (data not shown). These data indicate that production of IL-10 by CD45RBlow CD4+ cells is essential for cells within this population to mediate their immune-suppressive function.


An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.

Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F - J. Exp. Med. (1999)

Representative photomicrographs of the descending colon of RAG-2−/− mice after transfer of subpopulations of CD4+ T cells from WT or IL-10−/− mice. (A) Severe colitis in a mouse injected with CD45RBhigh CD4+ T cells from WT mice. (B) Normal appearance of the colon in a mouse restored with WT CD45RBhigh and WT CD45RBlow CD4+ T cells, indicating that the WT CD45RBlow population is able to inhibit disease induced by WT CD45RBhigh CD4+ T cells. (C) Severe colitis in a mouse cotransferred with WT CD45RBhigh CD4+ T cells and IL-10−/− CD45RBlow CD4+ cells, indicating that the IL-10−/− CD45RBlow subpopulation is unable to protect from the disease. (D) Severe colitis in a mouse receiving only IL-10−/− CD45RBlow cells, indicating that this population is able to induce disease. Hematoxylin and eosin; original magnifications: ×50.
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Related In: Results  -  Collection

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Figure 1: Representative photomicrographs of the descending colon of RAG-2−/− mice after transfer of subpopulations of CD4+ T cells from WT or IL-10−/− mice. (A) Severe colitis in a mouse injected with CD45RBhigh CD4+ T cells from WT mice. (B) Normal appearance of the colon in a mouse restored with WT CD45RBhigh and WT CD45RBlow CD4+ T cells, indicating that the WT CD45RBlow population is able to inhibit disease induced by WT CD45RBhigh CD4+ T cells. (C) Severe colitis in a mouse cotransferred with WT CD45RBhigh CD4+ T cells and IL-10−/− CD45RBlow CD4+ cells, indicating that the IL-10−/− CD45RBlow subpopulation is unable to protect from the disease. (D) Severe colitis in a mouse receiving only IL-10−/− CD45RBlow cells, indicating that this population is able to induce disease. Hematoxylin and eosin; original magnifications: ×50.
Mentions: To determine whether the CD45RBlow CD4+ population from IL-10−/− mice contained regulatory T cells, this population was compared with CD45RBlow CD4+ cells from WT mice for the ability to inhibit colitis induced in RAG-2−/− mice by transfer of WT CD45RBhigh CD4+ cells. Expression of CD45RB was similar on CD4+ T cells from 10–12-wk-old IL-10−/− and WT mice (data not shown). WT CD45RBhigh CD4+ cells (4 × 105) were transferred to syngeneic RAG-2−/− mice either alone or in combination with 2 × 105 CD45RBlow CD4+ cells from WT or IL-10−/− mice. As controls, the CD45RBlow CD4+ populations from IL-10−/− or WT mice were transferred alone and some mice were not reconstituted. 10–12 wk after T cell reconstitution, mice were killed and the development of colonic inflammation was assessed. As described previously 34, transfer of CD45RBhigh CD4+ cells into RAG-2−/− mice resulted in the development of severe colitis (Fig. 1 A) in the majority of mice (63.4%; Table , top). This colitis was characterized by an extensive inflammatory cell infiltrate, marked epithelial cell hyperplasia, and depletion of mucin-secreting cells. Cotransfer of the CD45RBlow CD4+ population significantly inhibited (P < 0.005) the development of colitis, as the majority of mice in this group (83.8%; Table , top) had minimal changes in the intestine (Fig. 1 B). In contrast, cotransfer of CD45RBlow CD4+ cells from IL-10−/− mice failed to protect mice from colitis, as the majority of mice in this group (64.2%; Table , top) developed intestinal inflammation (Fig. 1 C) identical to that seen in mice restored with CD45RBhigh CD4+ cells alone. Not only did the CD45RBlow population from IL-10−/− mice fail to protect from colitis, this population actually induced disease with similar characteristics (Fig. 1 D) and incidence (59.0%; Table , top) to that induced by WT CD45RBhigh CD4+ cells. As described previously 4, immune-deficient mice either unreconstituted or restored with WT CD45RBlow CD4+ cells exhibited no pathological changes in the intestine (data not shown). These data indicate that production of IL-10 by CD45RBlow CD4+ cells is essential for cells within this population to mediate their immune-suppressive function.

Bottom Line: The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody.Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population.These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom.

ABSTRACT
A T helper cell type 1-mediated colitis develops in severe combined immunodeficient mice after transfer of CD45RB(high) CD4(+) T cells and can be prevented by cotransfer of the CD45RB(low) subset. The immune-suppressive activities of the CD45RB(low) T cell population can be reversed in vivo by administration of an anti-transforming growth factor beta antibody. Here we show that interleukin (IL)-10 is an essential mediator of the regulatory functions of the CD45RB(low) population. This population isolated from IL-10-deficient (IL-10(-/-)) mice was unable to protect from colitis and when transferred alone to immune-deficient recipients induced colitis. Treatment with an anti-murine IL-10 receptor monoclonal antibody abrogated inhibition of colitis mediated by wild-type (WT) CD45RB(low) CD4(+) cells, suggesting that IL-10 was necessary for the effector function of the regulatory T cell population. Inhibition of colitis by WT regulatory T cells was not dependent on IL-10 production by progeny of the CD45RB(high) CD4(+) cells, as CD45RB(low) CD4(+) cells from WT mice were able to inhibit colitis induced by IL-10(-/-) CD45RB(high) CD4(+) cells. These findings provide the first clear evidence that IL-10 plays a nonredundant role in the functioning of regulatory T cells that control inflammatory responses towards intestinal antigens.

Show MeSH
Related in: MedlinePlus