title: Role of the programmed death-1 pathway in regulation of alloimmune responses in vivo.
abstract: Programmed death-1 (PD-1), an inhibitory receptor up-regulated on activated T cells, has been shown to play a critical immunoregulatory role in peripheral tolerance, but its role in alloimmune responses is poorly understood. Using a novel alloreactive TCR-transgenic model system, we examined the functions of this pathway in the regulation of alloreactive CD4+ T cell responses in vivo. PD-L1, but not PD-1 or PD-L2, blockade accelerated MHC class II-mismatched skin graft (bm12 (I-Abm12) into B6 (I-Ab)) rejection in a similar manner to CTLA-4 blockade. In an adoptive transfer model system using the recently described anti-bm12 (ABM) TCR-transgenic mice directly reactive to I-Abm12, PD-1 and PD-L1 blockade enhanced T cell proliferation early in the immune response. In contrast, at a later time point preceding accelerated allograft rejection, only PD-L1 blockade enhanced T cell proliferation. In addition, PD-L1 blockade enhanced alloreactive Th1 cell differentiation. Apoptosis of alloantigen-specific T cells was inhibited significantly by PD-L1 but not PD-1 blockade, indicating that PD-1 may not be the receptor for the apoptotic effect of the PD-L1-signaling pathway. Interestingly, the effect of PD-L1 blockade was dependent on the presence of CD4+ CD25+ regulatory T cells in vivo. These data demonstrate a critical role for the PD-1 pathway, particularly PD-1/PD-L1 interactions, in the regulation of alloimmune responses in vivo.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sigrid E
authors.initials: SE
authors.lastname: Sandner
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clarkson
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Alberto
authors.initials: A
authors.lastname: Sanchez-Fueyo
authors.forename: Christoph
authors.initials: C
authors.lastname: Domenig
authors.forename: Antje
authors.initials: A
authors.lastname: Habicht
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology; D007519:Isoantigens; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; D007519:Isoantigens; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D015375:Receptors, Interleukin-2