Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment

Low- or reduced-intensity conditioning regimens for allogeneic hemopoietic stem cell transplantation are effective at establishing donor hematopoietic engraftment and host-vs.-graft (HvG) tolerance. We investigated the mechanisms of HvG tolerance induction and maintenance in an animal model in which transplantation of sublethally irradiated female recipients with bone marrow (BM) from syngeneic male donors produces mixed chimerism. Splenocytes from chimeric mice inhibited HY-specific CD8⁺ T cell responses both in vitro and in vivo, and their adoptive transfer facilitated donor hematopoietic engraftment. These properties were contained within the CD4⁺CD25⁺ population. The conditioning protocol alone led to a proportional expansion of regulatory T cells (Tregs), but the inhibitory activity was induced only if male BM was infused. The administration of anti-CD25-depleting antibodies to conditioned recipients at time of BM transplantation prevented donor-recipient chimerism but did not affect engraftment if performed after the establishment of chimerism, thus indicating that recipient Tregs are required for the generation but not the maintenance of HvG tolerance. We conclude that donor-specific Tregs of recipient origin are recruited when the donor antigens are present during reduced-intensity conditioning-induced Treg expansion.