title: PD-1-dependent mechanisms maintain peripheral tolerance of donor-reactive CD8+ T cells to transplanted tissue.
abstract: Peripheral mechanisms of self-tolerance often depend on the quiescent state of the immune system. To what degree such mechanisms can be engaged in the enhancement of allograft survival is unclear. To examine the role of the PD-1 pathway in the maintenance of graft survival following blockade of costimulatory pathways, we used a single-Ag mismatch model of graft rejection where we could track the donor-specific cells as they developed endogenously and emerged from the thymus. We found that graft-specific T cells arising under physiologic developmental conditions at low frequency were actively deleted at the time of transplantation under combined CD28/CD40L blockade. However, this deletion was incomplete, and donor-specific cells that failed to undergo deletion up-regulated expression of PD-1. Furthermore, blockade of PD-1 signaling on these cells via in vivo treatment with anti-PD-1 mAb resulted in rapid expansion of donor-specific T cells and graft loss. These results suggest that the PD-1 pathway was engaged in the continued regulation of the low-frequency graft-specific immune response and thus in maintenance of graft survival.
authors.affiliation: Emory Transplant Center and Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Brent H
authors.initials: BH
authors.lastname: Koehn
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.forename: Ivana R
authors.initials: IR
authors.lastname: Ferrer
authors.forename: Keshawna
authors.initials: K
authors.lastname: Borom
authors.forename: Shivaprakash
authors.initials: S
authors.lastname: Gangappa
authors.forename: Allan D
authors.initials: AD
authors.lastname: Kirk
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000943:Antigens, Differentiation; D018106:CD28 Antigens; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D023201:CD40 Ligand