Abstract
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-beta. 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. (Blood. 2012; 119(24):5898-5908)