title: CD8+ T cells undergo activation and programmed death-1 repression in the liver of aged Ae2a,b-/- mice favoring autoimmune cholangitis.
abstract: Primary biliary cirrhosis (PBC) is a chronic cholestatic disease of unknown etiopathogenesis showing progressive autoimmune-mediated cholangitis. In PBC patients, the liver and lymphocytes exhibit diminished expression of AE2/SLC4A2, a Cl-/HCO3- anion exchanger involved in biliary bicarbonate secretion and intracellular pH regulation. Decreased AE2 expression may be pathogenic as Ae2a,b(-/-) mice reproduce hepatobiliary and immunological features resembling PBC. To understand the role of AE2 deficiency for autoimmunity predisposition we focused on the phenotypic changes of T cells that occur over the life-span of Ae2a,b(-/-) mice. At early ages (1-9 months), knockout mice had reduced numbers of intrahepatic T cells, which exhibited increased activation, programmed-cell-death (PD)-1 expression, and apoptosis. Moreover, young knockouts had upregulated PD-1 ligand (PD-L1) on bile-duct cells, and administration of neutralizing anti-PD-L1 antibodies prevented their intrahepatic T-cell deletion. Older (≥ 10 months) knockouts, however, showed intrahepatic accumulation of cytotoxic CD8(+) T cells with downregulated PD-1 and diminished apoptosis. In-vitro DNA demethylation with 5-aza-2'-deoxycytidine partially reverted PD-1 downregulation of intrahepatic CD8(+) T cells from aged knockouts.
  
  
  CONCLUSIONS
  Early in life, AE2 deficiency results in intrahepatic T-cell activation and PD-1/PD-L1 mediated deletion. With aging, intrahepatic CD8+ T cells epigenetically suppress PD-1, and their consequential expansion and further activation favor autoimmune cholangitis.
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Axel R
authors.initials: AR
authors.lastname: Concepcion
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: January T
authors.initials: JT
authors.lastname: Salas
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sáez
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Sarai
authors.initials: S
authors.lastname: Sarvide
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Ferrer
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Portu
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Iker
authors.initials: I
authors.lastname: Uriarte
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervás-Stubbs
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and CIBERehd, Pamplona, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Medina
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D027963:Chloride-Bicarbonate Antiporters / Q000172:deficiency / Q000235:genetics; D002761:Cholangitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017637:Clonal Deletion; D019175:DNA Methylation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014162:Transfection
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D027963:Chloride-Bicarbonate Antiporters; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C579495:Slc4a2 protein, mouse
keywords: Immune response; Immunity; Immunology and Microbiology Section; Na+-independent Cl−/HCO3− anion exchanger AE2; age-related changes; intracellular pH homeostasis; mouse model of autoimmune cholangitis; self-tolerance breakdown