Promoting regulation via the inhibition of DNAM-1 after transplantation

Motoko Koyama, Rachel D. Kuns, Stuart D. Olver, Katie E. Lineburg, Mary Lor, Bianca E. Teal, Neil C. Raffelt, Lucie Leveque, Christopher J. Chan, Renee J. Robb, Kate A. Markey, Kylie A. Alexander, Antiopi Varelias, Andrew D. Clouston, Mark J. Smyth, Kelli P.A. MacDonald, Geoffrey R. Hill

Donor T cells play pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects following bone marrow transplantation (BMT). DNAX accessory molecule 1 (DNAM-1) is a costimulatory and adhesion molecule, expressed mainly by natural killer cells and CD8(+) T cells at steady state to promote adhesion to ligand-expressing targets and enhance cytolysis. We have analyzed the role of this pathway in GVHD and GVL. The absence of DNAM-1 on the donor graft attenuated GVHD in major histocompatibility complex (MHC)-mismatched and MHC-matched BMT following conditioning with lethal and sublethal irradiation. In contrast, DNAM-1 was not critical for GVL effects against ligand (CD155) expressing and nonexpressing leukemia. The effects on GVHD following myeloablative conditioning were independent of CD8(+) T cells and dependent on CD4(+) T cells, and specifically donor FoxP3(+) regulatory T cells (Treg). The absence of DNAM-1 promoted the expansion and suppressive function of Treg after BMT. These findings provide support for therapeutic DNAM-1 inhibition to promote tolerance in relevant inflammatory-based diseases characterized by T-cell activation.