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,
Departments of
* Surgery and
Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Transplantation Research Center, Renal Division, Brigham and Women’s Hospital and Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115;
Gachon University of Medicine and Science, Incheon, Korea;
¶ Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and
|| Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104
Immune activation via TLRs is known to prevent transplantation tolerance in multiple animal models. To investigate the mechanisms underlying this barrier to tolerance induction, we used complementary murine models of skin and cardiac transplantation in which prolonged allograft acceptance is either spontaneous or pharmacologically induced with anti-CD154 mAb and rapamycin. In each model, we found that prolonged allograft survival requires the presence of natural CD4+Foxp3+ T regulatory cells (Tregs), and that the TLR9 ligand CpG prevents graft acceptance both by interfering with natural Treg function and by promoting the differentiation of Th1 effector T cells in vivo. We further demonstrate that although Th17 cells differentiate from naive alloreactive T cells, these cells do not arise from natural Tregs in either CpG-treated or untreated graft recipients. Finally, we show that CpG impairs natural Treg suppressor capability and prevents Treg-dependent allograft acceptance in an IL-6-independent fashion. Our data therefore suggest that TLR signals do not prevent prolonged graft acceptance by directing natural Tregs into the Th17 lineage or by using other IL-6-dependent mechanisms. Instead, graft destruction results from the ability of CpG to drive Th1 differentiation and interfere with immunoregulation established by alloreactive natural CD4+Foxp3+ Tregs.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 AI41521.
2 Address correspondence and reprint requests to Dr. Laurence A. Turka, 415 Curie Boulevard, Room 111, Philadelphia, PA 19104. E-mail address: turka{at}mail.med.upenn.edu
3 Abbreviations used in this paper: Treg, T regulatory cell; ABM, anti-bm12; MST, median survival time.
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