Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

TLDR

Acute graft‑versus‑host disease remains a major obstacle to allogeneic bone‑marrow transplantation, and CD4+CD25+ regulatory T cells can suppress alloantigen‑driven T‑cell responses in vitro and are required for donor‑cell tolerization. Donor CD4+CD25+ regulatory T cells isolated from spleen or bone marrow potently inhibited allo‑responses in vitro and prevented lethal aGVHD in irradiated BALB/c hosts, achieving >90 % suppression at a 1:1 ratio, an effect dependent on IL‑10 secretion and donor origin that underscores the importance of the donor Treg/conventional T cell balance.

Abstract

Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4+CD25+ regulatory T (Treg) 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-2b) 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-2d) hosts in vivo. The addition of the CD4+CD25+ Treg 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 Treg cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4+CD25+ Treg and conventional CD4+CD25− T cells can determine the outcome of aGVHD.