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Blood, 1 September 2008, Vol. 112, No. 5, pp. 2149-2155. Prepublished online as a Blood First Edition Paper on June 24, 2008; DOI 10.1182/blood-2007-12-127449. This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2007-12-127449v1 112/5/2149    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Haspot, F. Articles by Sykes, M. Search for Related Content PubMed PubMed Citation Articles by Haspot, F. Articles by Sykes, M. Related Collections Immunobiology Transplantation Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway Fabienne Haspot1, Thomas Fehr1, Carrie Gibbons1, Guiling Zhao1, Timothy Hogan1, Tasuku Honjo2, Gordon J. Freeman3, and Megan Sykes1 1 Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA; 2 Department of Medical Chemistry, Faculty of Medicine Kotzin, Kyoto University Yoshida-Konoe, Kyoto, Japan; and 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA Although 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 with rejecting CD8 cells) while being functionally silenced by day 4 after transplantation. Although both tolerized and rejecting alloreactive CD8 cells up-regulate 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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