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Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation.

Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S - J. Exp. Med. (2002)

Bottom Line: The addition of the CD4(+)CD25(+) T(reg) cells at a 1:1 ratio with responder/inducer CD4(+)CD25(-) T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD.This protective effect depended in part on the ability of the transferred CD4(+)CD25(+) T cells to secrete interleukin 10 and occurred if the T(reg) cells were of donor, but not host, origin.Our results demonstrate that the balance of donor-type CD4(+)CD25(+) T(reg) and conventional CD4(+)CD25(-) T cells can determine the outcome of aGVHD.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CA 94305, USA.

ABSTRACT
Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4(+)CD25(+) regulatory T (T(reg)) cells have recently been shown to suppress proliferative responses of CD4(+)CD25(-) T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4(+)CD25(+) T cells isolated from the spleen or BM of donor C57BL/6 (H-2(b)) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4(+)CD25(-) T cells in irradiated BALB/c (H-2(d)) hosts in vivo. The addition of the CD4(+)CD25(+) T(reg) cells at a 1:1 ratio with responder/inducer CD4(+)CD25(-) T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4(+)CD25(+) T cells to secrete interleukin 10 and occurred if the T(reg) cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4(+)CD25(+) T(reg) and conventional CD4(+)CD25(-) T cells can determine the outcome of aGVHD.

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(A) Comparison of the suppressive effects of responder- and stimulator-type CD4+CD25+ T cells on the alloresponses of BALB/c or C57BL/6 CD4+CD25− T cells in the MLR. Cultures were set up with 105 CD4+CD25− responder T cells and equal numbers of each of the remaining cell populations. The bars represent the means of triplicate values and the brackets indicate the SDs. **, P < 0.01 (Student's t test). One of two experiments with similar results is shown. (B) Comparison of the protective effect of CD4+CD25+ T cells from C57BL/6 and BALB/c animals in lethal aGVHD of BALB/c hosts induced by C57BL/6 CD4+CD25− T cells. BALB/c mice received 800 cGy TBI, 2 × 106 C57BL/6 TCD BM cells, and 4.5 × 105 C57BL/6 CD4+CD25− T cells with or without 4.5 × 105 CD4+CD25+ T cells from either C57BL/6 or BALB/c animals. Combined data from two independent experiments with 10 animals per group are shown.
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fig6: (A) Comparison of the suppressive effects of responder- and stimulator-type CD4+CD25+ T cells on the alloresponses of BALB/c or C57BL/6 CD4+CD25− T cells in the MLR. Cultures were set up with 105 CD4+CD25− responder T cells and equal numbers of each of the remaining cell populations. The bars represent the means of triplicate values and the brackets indicate the SDs. **, P < 0.01 (Student's t test). One of two experiments with similar results is shown. (B) Comparison of the protective effect of CD4+CD25+ T cells from C57BL/6 and BALB/c animals in lethal aGVHD of BALB/c hosts induced by C57BL/6 CD4+CD25− T cells. BALB/c mice received 800 cGy TBI, 2 × 106 C57BL/6 TCD BM cells, and 4.5 × 105 C57BL/6 CD4+CD25− T cells with or without 4.5 × 105 CD4+CD25+ T cells from either C57BL/6 or BALB/c animals. Combined data from two independent experiments with 10 animals per group are shown.

Mentions: It has been shown that CD4+CD25+ T cells need to be activated via their T cell receptor to be functional in vitro, i.e., suppress the response of CD4+CD25− or CD8+ T cells to antigenic or polyclonal stimuli (22, 23, 28). However, the nature of antigens recognized by CD4+CD25+ T cells and the prerequisites necessary for their activation, especially in the response to alloantigens, are still only poorly understood. To address this question we cocultured C57BL/6 splenic CD4+CD25− T cells and irradiated BALB/c stimulator cells in the presence of either C57BL/6 or BALB/c splenic CD4+CD25+ T cells at a 1:1 ratio. Whereas C57BL/6 Treg cells suppressed the proliferation of the C57BL/6 CD4+ CD25− T cells by >95%, BALB/c-derived Treg cells slightly enhanced the proliferation of the CD4+CD25− T cells (Fig. 6 A). A lack of suppression was also obtained when C57BL/6 CD4+CD25+ T cells were cocultured with BALB/c CD4+CD25− T cells as responder and C57BL/6 stimulator cells. Dieckmann et al. (41) obtained comparable results with human allogeneic CD4+CD25+ and CD4+CD25− T cells, if the stimulator cells and the CD4+CD25+ T cells originated from the same donor.


Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation.

Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S - J. Exp. Med. (2002)

(A) Comparison of the suppressive effects of responder- and stimulator-type CD4+CD25+ T cells on the alloresponses of BALB/c or C57BL/6 CD4+CD25− T cells in the MLR. Cultures were set up with 105 CD4+CD25− responder T cells and equal numbers of each of the remaining cell populations. The bars represent the means of triplicate values and the brackets indicate the SDs. **, P < 0.01 (Student's t test). One of two experiments with similar results is shown. (B) Comparison of the protective effect of CD4+CD25+ T cells from C57BL/6 and BALB/c animals in lethal aGVHD of BALB/c hosts induced by C57BL/6 CD4+CD25− T cells. BALB/c mice received 800 cGy TBI, 2 × 106 C57BL/6 TCD BM cells, and 4.5 × 105 C57BL/6 CD4+CD25− T cells with or without 4.5 × 105 CD4+CD25+ T cells from either C57BL/6 or BALB/c animals. Combined data from two independent experiments with 10 animals per group are shown.
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fig6: (A) Comparison of the suppressive effects of responder- and stimulator-type CD4+CD25+ T cells on the alloresponses of BALB/c or C57BL/6 CD4+CD25− T cells in the MLR. Cultures were set up with 105 CD4+CD25− responder T cells and equal numbers of each of the remaining cell populations. The bars represent the means of triplicate values and the brackets indicate the SDs. **, P < 0.01 (Student's t test). One of two experiments with similar results is shown. (B) Comparison of the protective effect of CD4+CD25+ T cells from C57BL/6 and BALB/c animals in lethal aGVHD of BALB/c hosts induced by C57BL/6 CD4+CD25− T cells. BALB/c mice received 800 cGy TBI, 2 × 106 C57BL/6 TCD BM cells, and 4.5 × 105 C57BL/6 CD4+CD25− T cells with or without 4.5 × 105 CD4+CD25+ T cells from either C57BL/6 or BALB/c animals. Combined data from two independent experiments with 10 animals per group are shown.
Mentions: It has been shown that CD4+CD25+ T cells need to be activated via their T cell receptor to be functional in vitro, i.e., suppress the response of CD4+CD25− or CD8+ T cells to antigenic or polyclonal stimuli (22, 23, 28). However, the nature of antigens recognized by CD4+CD25+ T cells and the prerequisites necessary for their activation, especially in the response to alloantigens, are still only poorly understood. To address this question we cocultured C57BL/6 splenic CD4+CD25− T cells and irradiated BALB/c stimulator cells in the presence of either C57BL/6 or BALB/c splenic CD4+CD25+ T cells at a 1:1 ratio. Whereas C57BL/6 Treg cells suppressed the proliferation of the C57BL/6 CD4+ CD25− T cells by >95%, BALB/c-derived Treg cells slightly enhanced the proliferation of the CD4+CD25− T cells (Fig. 6 A). A lack of suppression was also obtained when C57BL/6 CD4+CD25+ T cells were cocultured with BALB/c CD4+CD25− T cells as responder and C57BL/6 stimulator cells. Dieckmann et al. (41) obtained comparable results with human allogeneic CD4+CD25+ and CD4+CD25− T cells, if the stimulator cells and the CD4+CD25+ T cells originated from the same donor.

Bottom Line: The addition of the CD4(+)CD25(+) T(reg) cells at a 1:1 ratio with responder/inducer CD4(+)CD25(-) T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD.This protective effect depended in part on the ability of the transferred CD4(+)CD25(+) T cells to secrete interleukin 10 and occurred if the T(reg) cells were of donor, but not host, origin.Our results demonstrate that the balance of donor-type CD4(+)CD25(+) T(reg) and conventional CD4(+)CD25(-) T cells can determine the outcome of aGVHD.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, CA 94305, USA.

ABSTRACT
Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4(+)CD25(+) regulatory T (T(reg)) cells have recently been shown to suppress proliferative responses of CD4(+)CD25(-) T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4(+)CD25(+) T cells isolated from the spleen or BM of donor C57BL/6 (H-2(b)) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4(+)CD25(-) T cells in irradiated BALB/c (H-2(d)) hosts in vivo. The addition of the CD4(+)CD25(+) T(reg) cells at a 1:1 ratio with responder/inducer CD4(+)CD25(-) T cells resulted in a >90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4(+)CD25(+) T cells to secrete interleukin 10 and occurred if the T(reg) cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4(+)CD25(+) T(reg) and conventional CD4(+)CD25(-) T cells can determine the outcome of aGVHD.

Show MeSH
Related in: MedlinePlus