Identification and expansion of highly suppressive CD8 +FoxP3 + regulatory T cells after experimental allogeneic bone marrow transplantation

摘要

FoxP3 + confers suppressive properties and is confined to regulatory T cells (T reg) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4 + T reg are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8 + population of FoxP3 + T reg that convert from CD8 + conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8 + T reg undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4 +FoxP3 + population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8 +FoxP3 + T reg are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8 +FoxP3 + T reg thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation.