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PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells
Insights
Temporary depletion of CD4+ T cells prevents graft-versus-host disease (GVHD) while maintaining graft-versus-leukemia (GVL) effects. This strategy modulates programmed death ligand-1 (PD-L1) interactions to control immune responses post-transplant.
Area of Science:
- Immunology
- Transplantation Biology
- Cancer Immunotherapy
Background:
- Programmed death ligand-1 (PD-L1) regulates immune responses by interacting with PD-1 and CD80.
- PD-L1/CD80 interactions can worsen graft-versus-host disease (GVHD), while PD-1/CD80 costimulation ameliorates it.
Purpose of the Study:
- To investigate the therapeutic potential of transient CD4+ T cell depletion post-hematopoietic cell transplantation.
- To determine the impact of CD4+ T cell depletion on GVHD and graft-versus-leukemia (GVL) responses.
Main Methods:
- Utilized allogeneic and xenogeneic murine models of GVHD.
- Administered temporary depletion of donor CD4+ T cells early after transplantation.
- Analyzed serum cytokine levels (IFN-γ, IL-2) and PD-L1 expression on immune cells and tissues.
Main Results:
- CD4+ T cell depletion effectively prevented GVHD and preserved GVL effects.
- Depletion led to increased IFN-γ and decreased IL-2, upregulating PD-L1 expression.
- PD-L1/PD-1 interactions on CD8+ T cells in target tissues induced anergy, preventing GVHD.
- PD-L1/CD80 interactions in lymphoid tissues promoted CD8+ T cell expansion for GVL effects.
Conclusions:
- Transient CD4+ T cell depletion is a promising strategy for GVHD prevention with preserved GVL activity.
- The outcome of PD-L1 signaling in CD8+ T cells is context-dependent, influenced by CD4+ T cell presence, interacting receptor, and tissue microenvironment.
Abstract:
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.
