Oncotarget

Research Papers: Immunology:

CD8+ T cells undergo activation and programmed death-1 repression in the liver of aged Ae2a,b–/– mice favoring autoimmune cholangitis

Axel R. Concepcion _, January T. Salas, Elena Sáez, Sarai Sarvide, Alex Ferrer, Ainhoa Portu, Iker Uriarte, Sandra Hervás-Stubbs, Ronald P.J. Oude Elferink, Jesús Prieto and Juan F. Medina

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Oncotarget. 2015; 6:28588-28606. https://doi.org/10.18632/oncotarget.5665

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Abstract

Axel R. Concepcion1, January T. Salas2, Elena Sáez1, Sarai Sarvide1, Alex Ferrer3, Ainhoa Portu1, Iker Uriarte1, Sandra Hervás-Stubbs1, Ronald P.J. Oude Elferink4, Jesús Prieto1 and Juan F. Medina1

1 Center for Applied Medical Research (CIMA), School of Medicine and Clinic University of Navarra, and Ciberehd, Pamplona, Spain

2 Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

3 Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA

4 Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands

Correspondence to:

Juan F. Medina, email:

Jesús Prieto, email:

Keywords: Na+-independent Cl/HCO3 anion exchanger AE2, mouse model of autoimmune cholangitis, intracellular pH homeostasis, age-related changes, self-tolerance breakdown, Immunology and Microbiology Section, Immune response, Immunity

Received: August 24, 2015 Accepted: August 31, 2015 Published: September 15, 2015

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. Conclusion: 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.


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