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Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.

Read S, Malmström V, Powrie F - J. Exp. Med. (2000)

Bottom Line: Previous studies have failed to identify how CD25(+) Treg cells function in vivo.These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling.Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.

View Article: PubMed Central - PubMed

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

ABSTRACT
It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25(+)CD45RB(low)CD4(+)) as those that control autoimmunity. Previous studies have failed to identify how CD25(+) Treg cells function in vivo. Our studies reveal that the immune-suppressive function of these cells in vivo is dependent on signaling via the negative regulator of T cell activation cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as secretion of the immune-suppressive cytokine transforming growth factor beta. Strikingly, constitutive expression of CTLA-4 among CD4(+) cells was restricted primarily to Treg cells, suggesting that CTLA-4 expression by these cells is involved in their immune-suppressive function. These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling. Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.

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Regulation of colitis by CD25+CD4+ cells is TGF-β dependent. SCID mice received CD45RBhighCD4+ cells alone (□) or in combination with 105 CD25+ cells (▵). Mice also received either anti–TGF-β (filled symbols) or PBS (open symbols). Significant protection mediated by CD25+ cells (P < 0.01) abrogated by treatment with anti–TGF-β mAb (P < 0.02).
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Figure 4: Regulation of colitis by CD25+CD4+ cells is TGF-β dependent. SCID mice received CD45RBhighCD4+ cells alone (□) or in combination with 105 CD25+ cells (▵). Mice also received either anti–TGF-β (filled symbols) or PBS (open symbols). Significant protection mediated by CD25+ cells (P < 0.01) abrogated by treatment with anti–TGF-β mAb (P < 0.02).

Mentions: Extensive analysis of the immune-suppressive function of CD25+ Treg cells in vitro has shown no demonstrable role for the immune-suppressive cytokine TGF-β 1718. This was somewhat at odds with our previous observations that the ability of CD45RBlow cells to inhibit colitis was absolutely dependent on TGF-β 9. It is possible that this difference may reflect a comparison of the function of CD25+ cells with unseparated CD45RBlow cells. Given that we now show that Treg cells that most efficiently inhibit colitis are also CD25+, we directly tested whether TGF-β was required for the function of these cells in vivo. As with unseparated CD45RBlow cells, administration of anti–TGF-β to mice usually protected from colitis by transfer of a mixture of CD45RBhigh and CD25+CD45RBlow cells led to abrogation of suppression and induction of severe colitis in the recipients (Fig. 4). These data indicate that in contrast to immune suppression in vitro, immune suppression in vivo was absolutely dependent on TGF-β.


Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.

Read S, Malmström V, Powrie F - J. Exp. Med. (2000)

Regulation of colitis by CD25+CD4+ cells is TGF-β dependent. SCID mice received CD45RBhighCD4+ cells alone (□) or in combination with 105 CD25+ cells (▵). Mice also received either anti–TGF-β (filled symbols) or PBS (open symbols). Significant protection mediated by CD25+ cells (P < 0.01) abrogated by treatment with anti–TGF-β mAb (P < 0.02).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193261&req=5

Figure 4: Regulation of colitis by CD25+CD4+ cells is TGF-β dependent. SCID mice received CD45RBhighCD4+ cells alone (□) or in combination with 105 CD25+ cells (▵). Mice also received either anti–TGF-β (filled symbols) or PBS (open symbols). Significant protection mediated by CD25+ cells (P < 0.01) abrogated by treatment with anti–TGF-β mAb (P < 0.02).
Mentions: Extensive analysis of the immune-suppressive function of CD25+ Treg cells in vitro has shown no demonstrable role for the immune-suppressive cytokine TGF-β 1718. This was somewhat at odds with our previous observations that the ability of CD45RBlow cells to inhibit colitis was absolutely dependent on TGF-β 9. It is possible that this difference may reflect a comparison of the function of CD25+ cells with unseparated CD45RBlow cells. Given that we now show that Treg cells that most efficiently inhibit colitis are also CD25+, we directly tested whether TGF-β was required for the function of these cells in vivo. As with unseparated CD45RBlow cells, administration of anti–TGF-β to mice usually protected from colitis by transfer of a mixture of CD45RBhigh and CD25+CD45RBlow cells led to abrogation of suppression and induction of severe colitis in the recipients (Fig. 4). These data indicate that in contrast to immune suppression in vitro, immune suppression in vivo was absolutely dependent on TGF-β.

Bottom Line: Previous studies have failed to identify how CD25(+) Treg cells function in vivo.These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling.Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.

View Article: PubMed Central - PubMed

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

ABSTRACT
It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25(+)CD45RB(low)CD4(+)) as those that control autoimmunity. Previous studies have failed to identify how CD25(+) Treg cells function in vivo. Our studies reveal that the immune-suppressive function of these cells in vivo is dependent on signaling via the negative regulator of T cell activation cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as secretion of the immune-suppressive cytokine transforming growth factor beta. Strikingly, constitutive expression of CTLA-4 among CD4(+) cells was restricted primarily to Treg cells, suggesting that CTLA-4 expression by these cells is involved in their immune-suppressive function. These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling. Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.

Show MeSH
Related in: MedlinePlus