title: Analysis of the role of negative T cell costimulatory pathways in CD4 and CD8 T cell-mediated alloimmune responses in vivo.
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.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, MA 02115, USA.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Ito
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueno
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clarkson
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: Mollie M
authors.initials: MM
authors.lastname: Jurewicz
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Hugh
authors.initials: H
authors.lastname: Auchincloss
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D000943:Antigens, Differentiation / Q000276:immunology / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology / Q000502:physiology; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; D018106:CD28 Antigens / Q000235:genetics; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D060908:CTLA-4 Antigen; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; D018106:CD28 Antigens; D015704:CD4 Antigens; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor