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The Journal of Immunology, 2005, 174: 6648-6656.
Copyright © 2005 by The American Association of Immunologists

Analysis of the Role of Negative T Cell Costimulatory Pathways in CD4 and CD8 T Cell-Mediated Alloimmune Responses In Vivo1

Toshiro Ito2,*,{ddagger}, Takuya Ueno2,*, Michael R. Clarkson*, Xueli Yuan*, Mollie M. Jurewicz*, Hideo Yagita§, Miyuki Azuma, Arlene H. Sharpe{dagger}, Hugh Auchincloss, Jr{ddagger}, Mohamed H. Sayegh* and Nader Najafian3,*

* Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital Boston, {dagger} Harvard Medical School, Boston, MA 02115; {ddagger} Department of Surgery, Massachusetts General Hospital, Boston, MA 02114; § Department of Immunology, Juntendo University School of Medicine, and Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan

Negative costimulatory signals mediated via cell surface molecules such as CTLA-4 and programmed death 1 (PD-1) play a critical role in down-modulating immune responses and maintaining peripheral tolerance. However, their role in alloimmune responses remains unclear. This study examined the role of these inhibitory pathways in regulating CD28-dependent and CD28-independent CD4 and CD8 alloreactive T cells in vivo. CTLA-4 blockade accelerated graft rejection in C57BL/6 wild-type recipients and in a proportion of CD4–/– but not CD8–/– recipients of BALB/c hearts. The same treatment led to prompt rejection in CD28–/– and a smaller proportion of CD4–/–CD28–/– mice with no effect in CD8–/–CD28–/– recipients. These results indicate that the CTLA-4:B7 pathway provides a negative signal to alloreactive CD8+ T cells, particularly in the presence of CD28 costimulation. In contrast, PD-1 blockade led to accelerated rejection of heart allografts only in CD28–/– and CD8–/–CD28–/– recipients. Interestingly, PD-1 ligand (PD-L1) blockade led to accelerated rejection in wild-type mice and in all recipients lacking CD28 costimulation. This effect was accompanied by expansion of IFN-{gamma}-producing alloreactive T cells and enhanced generation of effector T cells in rejecting allograft recipients. Thus, the PD-1:PD-L1 pathway down-regulates alloreactive CD4 T cells, particularly in the absence of CD28 costimulation. The differential effects of PD-1 vs PD-L1 blockade support the possible existence of a new receptor other than PD-1 for negative signaling through PD-L1. Furthermore, PD-1:PD-L1 pathway can regulate alloimmune responses independent of an intact CD28/CTLA-4:B7 pathway. Harnessing physiological mechanisms that regulate alloimmunity should lead to development of novel strategies to induce durable and reproducible transplantation tolerance.




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