Journal
ONCOTARGET
Volume 6, Issue 30, Pages 28588-28606Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.5665
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
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Funding
- UTE for CIMA Project
- Spanish Ministry of Science and Innovation [SAF2006-07818, SAF2009-11538, SAF2012-35455]
- Carlos III Institute of Health [Ciberehd CB06/04/0067]
- Subprogram Torres Quevedo (Spanish Ministry of Science and Innovation) [PTQ-10-04247]
- Subprogram Torres Quevedo (European Union) [PTQ-10-04247]
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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 Ae2(a,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 Ae2(a,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/PDL1 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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