title: Cutting edge: identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade.
abstract: Programmed death-1 (PD-1) promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD ligand 1 (PD-L1) regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune-susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in type 1 diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additionally, PD-L1 was critical for induction, but not maintenance, of CD8 T cell intestinal tolerance. PD-L1 blockade enhanced functionality of effector T cells, whereas established tolerant or anergic T cells were not dependent on PD-1/PD-L1 signaling to remain unresponsive. This highlights the existence of Ag-experienced T cell subsets that do not rely on PD-1/PD-L1 regulation. These findings illustrate how positive treatment outcomes and autoimmunity development during PD-1/PD-L1 inhibition are linked to the differentiation state of a T cell.
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.|University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pauken
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Nelson
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Tijana
authors.initials: T
authors.lastname: Martinov
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Spanier
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: James R
authors.initials: JR
authors.lastname: Heffernan
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Nathanael L
authors.initials: NL
authors.lastname: Sahli
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Clare F
authors.initials: CF
authors.lastname: Quarnstrom
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Osum
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Schenkel
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.affiliation: Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Vaiva
authors.initials: V
authors.lastname: Vezys
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Fife
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017635:Clonal Anergy; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology / Q000473:pathology; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor