Effector role of neonatal hepatic CD8+ lymphocytes in epithelial injury and autoimmunity in experimental biliary atresia |
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Authors: | Shivakumar Pranavkumar Sabla Gregg Mohanty Sujit McNeal Monica Ward Richard Stringer Keith Caldwell Charles Chougnet Claire Bezerra Jorge A |
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Institution: | Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA. |
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Abstract: | BACKGROUND & AIMS: Lymphocytes populate the livers of infants with biliary atresia, but it is unknown whether neonatal lymphocytes regulate pathogenesis of disease. Here, we investigate this question by examining the role of T lymphocytes in the destruction of extrahepatic bile ducts of neonatal mice using an experimental model of biliary atresia. METHODS: Inoculation of neonatal mice with rhesus rotavirus followed by multistaining flow cytometry to quantify expression of interferon-gamma by hepatic lymphocytes, and real-time polymerase chain reaction for mRNA expression of pro-inflammatory cytokines. This was followed by determining the consequences of antibody-mediated depletion of lymphocyte subtypes on the development of biliary obstruction, and coculture and cell transfer experiments to investigate the effector role of lymphocyte subtypes on neonatal biliary disease. RESULTS: Rotavirus infection results in overexpression of interferon-gamma by neonatal hepatic T cells. Among these cells, depletion of CD4(+) cells did not change the course of inflammatory injury and obstruction of neonatal bile ducts. In contrast, loss of CD8(+) cells remarkably suppressed duct injury, prevented luminal obstruction, and restored bile flow. Coculture experiments showed that rotavirus-primed, but not na?ve, CD8(+) cells were cytotoxic to cholangiocytes. In adoptive transfer experiments, we found that primed CD8(+) cells preferentially homed to extrahepatic bile ducts of neonatal mice and invaded their epithelial lining. CONCLUSIONS: Primed neonatal CD8(+) cells can activate a pro-inflammatory program, target diseased and healthy duct epithelium, and drive the phenotypic expression of biliary atresia, thus constituting a potential therapeutic target to halt disease progression. |
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Keywords: | IFNγ interferon-gamma IL interleukin mCL murine cholangiocyte cell line NK natural killer PCR polymerase chain reaction RRV rhesus rotavirus TNFα tumor necrosis factor alpha |
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