Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor CD4+ T cells increased serum IFN-γ but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor CD8+ T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment CD8+ T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1–mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptor expressed by CD8+ T cells, and the tissue environment in which the signaling occurs.
Xiong Ni, Qingxiao Song, Kaniel Cassady, Ruishu Deng, Hua Jin, Mingfeng Zhang, Haidong Dong, Stephen Forman, Paul J. Martin, Yuan-Zhong Chen, Jianmin Wang, Defu Zeng
Three injections of anti-CD4 prevent both acute and chronic GVHD and preserve GVL effects after HCT with C57BL/6 donors and BALB/c recipients.
Lethally irradiated BALB/c recipients transplanted with splenocytes (5 × 106) and TCD-BM (2.5 × 106) from C57BL/6 donors. Recipients were challenged with i.p. injection of BCL1/Luc cells (5 × 106 per mouse) and were given 3 i.v. injections of rat IgG or anti-CD4 mAb (500 μg/mouse) at days 0, 14, and 28 after HCT. Recipients given TCD-BM cells (2.5 × 106) alone were used as controls. Mice were monitored for tumor growth using in vivo bioluminescent imaging (BLI), clinical signs of GVHD, and survival. (