These authors contributed equally to this work.
The Programmed Death (PD)-1/PD-Ligand 1 Pathway Regulates Graft-Versus-Host-Reactive CD8 T Cells After Liver Transplantation
Article first published online: 25 SEP 2008
© 2008 The Authors Journal compilation © 2008 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 8, Issue 11, pages 2434–2444, November 2008
How to Cite
Schuchmann, M., Meyer, R. G., Distler, E., Von Stebut, E., Kuball, J., Schnürer, E., Wölfel, T., Theobald, M., Konur, A., Gregor, S., Schreiner, O., Huber, C., Galle, P. R., Otto, G. and Herr, W. (2008), The Programmed Death (PD)-1/PD-Ligand 1 Pathway Regulates Graft-Versus-Host-Reactive CD8 T Cells After Liver Transplantation. American Journal of Transplantation, 8: 2434–2444. doi: 10.1111/j.1600-6143.2008.02401.x
- Issue published online: 9 OCT 2008
- Article first published online: 25 SEP 2008
- Received 21 May 2008, revised 15 July 2008 and accepted for publication 30 July 2008
- Alloreactive T cells;
- graft-versus-host disease (GVHD);
- liver transplantation;
Acute graft-versus-host disease (aGVHD) is a life-threatening complication after solid-organ transplantation, which is mediated by host-reactive donor T cells emigrating from the allograft. We report on two liver transplant recipients who developed an almost complete donor chimerism in peripheral blood and bone marrow-infiltrating T cells during aGVHD. By analyzing these T cells directly ex vivo, we found that they died by apoptosis over time without evidence of rejection by host T cells. The host-versus-donor reactivity was selectively impaired, as anti-third-party and antiviral T cells were still detectable in the host repertoire. These findings support the acquired donor-specific allotolerance concept previously established in animal transplantation studies. We also observed that the resolution of aGVHD was not accompanied by an expansion of circulating immunosuppressive CD4/CD25/FoxP3-positive T cells. In fact, graft-versus-host-reactive T cells were controlled by an alternative negative regulatory pathway, executed by the programmed death (PD)-1 receptor and its ligand PD-L1. We found high PD-1 expression on donor CD4 and CD8 T cells. In addition, blocking PD-L1 on host-derived cells significantly enhanced alloreactivity by CD8 T cells in vitro. We suggest the interference with the PD-1/PD-L1 pathway as a therapeutic strategy to control graft-versus-host-reactive T cells in allograft recipients.