Human regulatory T cells control xenogeneic graft-versus-host disease induced by autologous T cells in RAG2-/-γc-/- immunodeficient mice

Purpose: Effective prevention of graft-versus-host disease (GvHD) is a major challenge to improve the safety of allogeneic stem cell transplantation for leukemia treatment. In murine transplantation models, administration of naturally occurring CD4(+)CD25(+) regulatory T cells (Treg) can prevent GvHD. Toward understanding the role of human Treg in stem cell transplantation, we studied their capacity to modulate T-cell - dependent xenogeneic (x) -GvHD in a new model where x-GvHD is induced in RAG2(-/-) gamma c(-/-) mice by i.v. administration of human peripheral blood mononuclear cells (PBMC). Experimental Design: Human PBMC, depleted of or supplemented with autologous CD25(+) Tregs, were administered in mice at different doses. The development of x-GvHD, in vivo expansion of human T cells, and secretion of human cytokines were monitored at weekly intervals. Results: Depletion of CD25(+) cells from human PBMC significantly exacerbated x-GvHD and accelerated its lethality. In contrast, coadministration of Treg-enriched CD25(+) cell fractions with autologous PBMC significantly reduced the lethality of x-GvHD. Treg administration significantly inhibited the explosive expansion of effector CD4(+) and CD8(+) T cells. Interestingly, protection from x-GvHD after Treg administration was associated with a significant increase in plasma levels of interleukin-10 and IFN-gamma, suggesting the de novo development of TR1 cells. Conclusions: These results show, for the first time, the potent in vivo capacity of naturally occur ring human Tregs to control GvHD-inducing autologous T cells, and indicate that this xenogeneic in vivo model may provide a suitable platform to further explore the in vivo mechanisms of T-cell down-regulation by naturally occurring human Tregs.