@article {542536, title = {Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo.}, journal = {J Immunol}, volume = {174}, number = {11}, year = {2005}, month = {2005 Jun 1}, pages = {6648-56}, abstract = {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.}, keywords = {Animals, Antibodies, Blocking, Antigens, CD, Antigens, CD274, Antigens, CD28, Antigens, CD4, Antigens, CD8, Antigens, CD80, Antigens, CD86, Antigens, Differentiation, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, CTLA-4 Antigen, Down-Regulation, Graft Rejection, Heart Transplantation, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Signal Transduction}, issn = {0022-1767}, author = {Ito, Toshiro and Ueno, Takuya and Clarkson, Michael R and Yuan, Xueli and Jurewicz, Mollie M and Yagita, Hideo and Azuma, Miyuki and Sharpe, Arlene H and Auchincloss, Hugh and Sayegh, Mohamed H and Najafian, Nader} }