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, Juan F. Medina

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)28588-28606
Number of pages19
JournalOncotarget
Volume6
Issue number30
DOIs
StatePublished - 2015

Keywords

  • Age-related changes
  • Immune response
  • Immunity
  • Immunology and Microbiology Section
  • Intracellular pH homeostasis
  • Mouse model of autoimmune cholangitis
  • Na-independent Cl/HCO3 anion exchanger AE2
  • Self-tolerance breakdown

ASJC Scopus subject areas

  • Oncology

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