PDL1 Is Required for Peripheral Transplantation Tolerance and Protection from Chronic Allograft Rejection

• Published in: Journal of Immunology Vol. 179; no. 8; pp. 5204 - 5210
• Main Authors: Tanaka, Katsunori, Albin, Monica J, Yuan, Xueli, Yamaura, Kazuhiro, Habicht, Antje, Murayama, Takaya, Grimm, Martin, Waaga, Ana Maria, Ueno, Takuya, Padera, Robert F, Yagita, Hideo, Azuma, Miyuki, Shin, Tahiro, Blazar, Bruce R, Rothstein, David M, Sayegh, Mohamed H, Najafian, Nader
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-10-2007
• Subjects: Abatacept; Animals; B7-1 Antigen - genetics; B7-1 Antigen - physiology; B7-H1 Antigen; Chronic Disease; Graft Rejection - immunology; Graft Rejection - pathology; Graft Rejection - prevention & control; H-2 Antigens - genetics; H-2 Antigens - immunology; Heart Transplantation - immunology; Heart Transplantation - pathology; Immunoconjugates - therapeutic use; Lymphocyte Culture Test, Mixed; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Peptides - antagonists & inhibitors; Peptides - deficiency; Peptides - genetics; Peptides - physiology; Programmed Cell Death 1 Ligand 2 Protein; Radiation Chimera; Skin Transplantation - immunology; Transplantation Tolerance - genetics; Transplantation Tolerance - immunology
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.179.8.5204

The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-gamma-producing alloreactive T cells and expansion of effector CD8(+) T cells in the periphery, and a decline in the percentage of Foxp3(+) graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.