The role of regulatory T cells in GVL and GVHD

The recognition and elimination of malignant cells by donor derived immune effector cells, the so-called graft-versus-leukemia effect (GVL), is key to the success of Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) in hematological malignancies. The ongoing challenge limiting the success of AHSCT is the maximization of this powerful GVL effect, while minimizing attack of the donor immune cells against the host normal tissue, the so-called graft-versus-host disease (GVHD). The role of CD4+CD25+FOXP3+ regulatory T cells (Treg) in the promotion of peripheral tolerance to self and thus the aversion of autoimmunity is now widely accepted. Furthermore, increasing evidence support their role in modulating alloresponses in the stem cell transplant setting, demonstrating that Tregs are critical players both in the engraftment of donor stem cells and the abrogation of allo-reactive responses that can result in GVHD. Importantly evidence from both murine models and human data suggests that Tregs dampen the alloresponse to host, thereby ameliorating the severity of GVHD without an apparent loss of useful GVL effect. This observation has sparked much research interest into both the underlying mechanisms by which Tregs mediate this effect and ways in which their function can be harnessed and translated into therapies to improve AHSCT outcomes. In this review we seek to summarize the existing data on the role of regulatory T cells in the stem cell transplant setting and examine how their manipulation might be incorporated as a useful technique to reduce GVHD following allogeneic stem cell transplantation.