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CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade.

Taylor PA, Noelle RJ, Blazar BR - J. Exp. Med. (2001)

Bottom Line: To determine whether CD4(+)CD25(+) cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4(+) T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte-associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo.CD4(+)CD25(+) T cells were found to be potent regulators of alloresponses.These data are the first to indicate that CD4(+)CD25(+) cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

View Article: PubMed Central - PubMed

Affiliation: University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, 420 SE Delaware St., Minneapolis, MN 55455, USA.

ABSTRACT
Immune regulatory CD4(+)CD25(+) cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4(+)CD25(+) cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4(+) T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte-associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4(+)CD25(+) T cells were found to be potent regulators of alloresponses. Depletion of CD4(+)CD25(+) T cells from the CD4(+) responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4(+)CD25(+) T cells to CD4(+)CD25(-) cultures restored tolerance induction. These data are the first to indicate that CD4(+)CD25(+) cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

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CD4+CD25+ cells upregulate CD40L on their cell surface during incubation with allostimulators. CD4+CD25− (top) and CD4+ CD25+ (bottom) cells were phenotyped for constitutive and inducible expression of CD40L. Dotted line indicates negative control. The thin solid line indicates the constitutive expression of freshly purified naive cells. The bold line indicates CD40L expression after 4-d incubation with allostimulators.
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Figure 3: CD4+CD25+ cells upregulate CD40L on their cell surface during incubation with allostimulators. CD4+CD25− (top) and CD4+ CD25+ (bottom) cells were phenotyped for constitutive and inducible expression of CD40L. Dotted line indicates negative control. The thin solid line indicates the constitutive expression of freshly purified naive cells. The bold line indicates CD40L expression after 4-d incubation with allostimulators.

Mentions: To determine whether CD40L was expressed on CD4+CD25+ cells, we examined cell surface expression of CD40L on fresh, naive CD4+CD25+ cells and CD4+ CD25− cells (Fig. 3). Although there was only a very modest increase in constitutive expression of CD40L on CD25+ cells as compared with CD25− cells, by day 4 of culture with allostimulators 69% of purified CD4+CD25+ cells expressed CD40L. In contrast, a lower proportion (30%) of CD4+CD25− cells expressed CD40L. These data demonstrate that CD40L is expressed on a high proportion of CD4+CD25+ cells after alloantigen stimulation and suggest that the CD40L/CD40 pathway may play an important role in the regulation of alloresponses in CD4+CD25+ cells.


CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade.

Taylor PA, Noelle RJ, Blazar BR - J. Exp. Med. (2001)

CD4+CD25+ cells upregulate CD40L on their cell surface during incubation with allostimulators. CD4+CD25− (top) and CD4+ CD25+ (bottom) cells were phenotyped for constitutive and inducible expression of CD40L. Dotted line indicates negative control. The thin solid line indicates the constitutive expression of freshly purified naive cells. The bold line indicates CD40L expression after 4-d incubation with allostimulators.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193378&req=5

Figure 3: CD4+CD25+ cells upregulate CD40L on their cell surface during incubation with allostimulators. CD4+CD25− (top) and CD4+ CD25+ (bottom) cells were phenotyped for constitutive and inducible expression of CD40L. Dotted line indicates negative control. The thin solid line indicates the constitutive expression of freshly purified naive cells. The bold line indicates CD40L expression after 4-d incubation with allostimulators.
Mentions: To determine whether CD40L was expressed on CD4+CD25+ cells, we examined cell surface expression of CD40L on fresh, naive CD4+CD25+ cells and CD4+ CD25− cells (Fig. 3). Although there was only a very modest increase in constitutive expression of CD40L on CD25+ cells as compared with CD25− cells, by day 4 of culture with allostimulators 69% of purified CD4+CD25+ cells expressed CD40L. In contrast, a lower proportion (30%) of CD4+CD25− cells expressed CD40L. These data demonstrate that CD40L is expressed on a high proportion of CD4+CD25+ cells after alloantigen stimulation and suggest that the CD40L/CD40 pathway may play an important role in the regulation of alloresponses in CD4+CD25+ cells.

Bottom Line: To determine whether CD4(+)CD25(+) cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4(+) T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte-associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo.CD4(+)CD25(+) T cells were found to be potent regulators of alloresponses.These data are the first to indicate that CD4(+)CD25(+) cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

View Article: PubMed Central - PubMed

Affiliation: University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, 420 SE Delaware St., Minneapolis, MN 55455, USA.

ABSTRACT
Immune regulatory CD4(+)CD25(+) cells play a vital role in the induction and maintenance of self-tolerance and are essential for T cell homeostasis and the prevention of autoimmunity. Induction of tolerance to allogeneic donor grafts is a clinically desirable goal in bone marrow and solid organ transplantation. To determine whether CD4(+)CD25(+) cells regulate T cell responses to alloantigen and are critical for tolerance induction, murine CD4(+) T cells were tolerized to alloantigen via ex vivo CD40 ligand (CD40L)/CD40 or CD28/cytotoxic T lymphocyte-associated antigen 4/B7 blockade resulting in secondary mixed leukocyte reaction hyporesponsiveness and tolerance to alloantigen in vivo. CD4(+)CD25(+) T cells were found to be potent regulators of alloresponses. Depletion of CD4(+)CD25(+) T cells from the CD4(+) responder population completely abrogated ex vivo tolerance induction to alloantigen as measured by intact responses to alloantigen restimulation in vitro and in vivo. Addback of CD4(+)CD25(+) T cells to CD4(+)CD25(-) cultures restored tolerance induction. These data are the first to indicate that CD4(+)CD25(+) cells are essential for the induction of tolerance to alloantigen and have important implications for tolerance-inducing strategies targeted at T cell costimulatory pathways.

Show MeSH
Related in: MedlinePlus