title: Disruption of CD154:CD40 blocks generation of allograft immunity without affecting APC activation.
abstract: CD154 (CD40 ligand, gp39) interaction with its receptor CD40 has been shown to be critically important for the generation of cell-mediated as well as humoral immunity. It has been proposed that ligation of CD40 on APCs, presumably by activated Th cells, leads to increased APC function as defined by up-regulation of costimulatory molecules and enhancement of IL-12 production. In this report, we directly examined the contribution of the CD154:CD40 pathway in a murine model of allograft rejection. Generation of both the CTL and alloantibody responses following injection with allogeneic P815 tumor cells was severely compromised in CD154 knockout mice and wild-type C57BL/6 mice treated with the anti-CD154 mAb, MR1. Splenic production of IL-2, IFN-gamma, and TNF was significantly suppressed from CD154-deficient mice, indicating a lack of T cell priming. However, splenic cells from CD154 knockout mice induced comparable levels of CD86 expression and IL-12 production when compared with their wild-type littermates. The treatment of CD154-/- mice with the agonistic anti-CD40 mAb, FGK45, generated activated APCs yet failed to restore either the CTL or alloantibody responses to P815. Likewise, immunization with B7-transfected P815 tumor cells failed to generate expansion of the CTL effector population in CD154-/- mice. These results suggest that the generation of allograft immunity is dependent on the interaction of CD154 with CD40 but not primarily for the activation of APCs.
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis 97331, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Shepherd
authors.forename: N I
authors.initials: NI
authors.lastname: Kerkvliet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000938:Antigen-Presenting Cells / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D007111:Immunity, Cellular / Q000235:genetics; D007114:Immunization; D007274:Injections, Intraperitoneal; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D012515:Mast-Cell Sarcoma; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009368:Neoplasm Transplantation / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand