Submitted December 5, 2007
Accepted April 20, 2008
Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway
Fabienne Haspot, Thomas Fehr, Carrie Gibbons, Guiling Zhao, Timothy Hogan, Tasuku Honjo, Gordon J. Freeman, and Megan Sykes*
Massachusetts General Hospital/Harvard Medical School, Transplantation Biology Research Center, Boston, MA, United States
Dept. of Medical Chemistry, Faculty of Medicine Kotzin, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto, Japan
Dana-Farber Cancer Institute/Harvard Medical School, Dept of Medical Oncology/Dept of Medicine, Boston, MA, United States
* Corresponding author; email: megan.sykes{at}tbrc.mgh.harvard.edu.
While interaction between programmed death-1 (PD-1) and the ligand PD-L1 has been shown to mediate CD8 cell exhaustion in the setting of chronic infection or the absence of CD4 help, a role for this pathway in attenuating early alloreactive CD8 cell responses has not been identified. We demonstrate that the PD-1/PD-L1 pathway is needed to rapidly tolerize alloreactive CD8 cells in a model that requires CD4 cells and culminates in CD8 cell deletion. This protocol involves allogeneic bone marrow transplantation (BMT) following conditioning with low-dose total body irradiation and anti-CD154 antibody. Tolerized donor-reactive T cell receptor transgenic CD8 cells are shown to be in an abortive activation state prior to their deletion, showing early and prolonged expression of activation markers (compared to rejecting CD8 cells) while being functionally silenced by Day 4 after transplantation. Although both tolerized and rejecting alloreactive CD8 cells upregulate PD-1, CD8 cell tolerance is dependent on the PD-1/PD-L1 pathway. In contrast, CD4 cells are tolerized independently of this pathway following BMT with anti-CD154. These studies demonstrate a dichotomy between the requirements for CD4 and CD8 tolerance and identify a role for PD-1 in the rapid tolerization of an alloreactive T cell population via a deletional mechanism.
