CC chemokine receptor 8 potentiates donor T_reg survival and is critical for the prevention of murine graft-versus-host disease

The infusion of donor regulatory T cells (T_regs) has been used to prevent acute graftversus- host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early T_reg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where T_regs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 T_reg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor T_reg function in the transplant setting. Donor T_regs lacking CCR8 (CCR8^-/-), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue T_regs from apoptosis. Instead, CCR8 potentiated T_reg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c1 antigen-presenting cells (APCs) were important for promoting donor T_reg maintenance after transplant. In contrast, host CD11c1 APCs appeared to be dispensable for early activation and expansion of donor T_regs. Collectively, our data indicate that a sustained donor T_reg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c1 APCs.