Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 196, Issue 3, Pages 389-399Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20020399
Keywords
immune regulation; T lymphocytes; IL-10; mixed leukocyte reaction; alloimmunity
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Funding
- NCI NIH HHS [R01 CA65237, R01 CA065237, R01 CA92225, R01 CA092225] Funding Source: Medline
- NHLBI NIH HHS [P01 HL057443, R01 HL58520, P01 HL57443] Funding Source: Medline
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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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