Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia

TLDR

CD4+CD25+ regulatory T cells prevent organ‑specific autoimmunity and induce transplant tolerance, yet clinical use is limited by the difficulty of obtaining sufficient numbers from a single donor. We expanded Tregs ex vivo by stimulating them with allogeneic antigen‑presenting cells, generating alloantigen‑specific regulatory T cells. Recipient‑type specific Tregs suppress graft‑versus‑host disease, promote immune reconstitution, preferentially survive in grafts, and retain graft‑versus‑tumor activity, indicating their potential for future clinical trials.

Abstract

CD4+CD25+ regulatory T cells (Treg's) play a pivotal role in preventing organ-specific autoimmune diseases and in inducing tolerance to allogeneic organ transplants. We and others recently demonstrated that high numbers of Treg's can also modulate graft-versus-host disease (GVHD) if administered in conjunction with allogeneic hematopoietic stem cell transplantation in mice. In a clinical setting, it would be impossible to obtain enough freshly purified Treg's from a single donor to have a therapeutic effect. Thus, we performed regulatory T cell expansion ex vivo by stimulation with allogeneic APCs, which has the additional effect of producing alloantigen-specific regulatory T cells. Here we show that regulatory T cells specific for recipient-type alloantigens control GVHD while favoring immune reconstitution. Irrelevant regulatory T cells only mediate a partial protection from GVHD. Preferential survival of specific regulatory T cells, but not of irrelevant regulatory T cells, was observed in grafted animals. Additionally, the use of specific regulatory T cells was compatible with some form of graft-versus-tumor activity. These data suggest that recipient-type specific Treg's could be preferentially used in the control of GVHD in future clinical trials.