Human CD8+ Regulatory T Cells Inhibit GVHD and Preserve General Immunity in Humanized Mice

Graft-versus-host disease (GVHD) is a lethal complication of allogeneic bone marrow transplantation (BMT). Immuno-suppressive agents are currently used to control GVHD but may cause general immune suppression and limit the effectiveness of BMT. Adoptive transfer of regulatory T cells (T-regs) can prevent GVHD in rodents, suggesting a therapeutic potential of T-regs for GVHD in humans. However, the clinical application of T-reg-based therapy is hampered by the low frequency of human T-regs and the lack of a reliable model to test their therapeutic effects in vivo. Recently, we successfully generated human alloantigen-specific CD8(hi) T-regs in a large scale from antigenically naive precursors ex vivo using allogeneic CD40-activated B cells as stimulators. We report a human allogeneic GVHD model established in humanized mice to mimic GVHD after BMT in humans. We demonstrate that ex vivo-induced CD8(hi) T-regs controlled GVHD in an allospecific manner by reducing alloreactive T cell proliferation as well as decreasing inflammatory cytokine and chemokine secretion within target organs through a CTLA-4-dependent mechanism in humanized mice. These CD8(hi) T-regs induced long-term tolerance effectively without compromising general immunity and graft-versus-tumor activity. Our results support testing of human CD8(hi) T-regs in GVHD in clinical trials.