TY - JOUR
T1 - Effector Role of Neonatal Hepatic CD8+ Lymphocytes in Epithelial Injury and Autoimmunity in Experimental Biliary Atresia
AU - Shivakumar, Pranavkumar
AU - Sabla, Gregg
AU - Mohanty, Sujit
AU - McNeal, Monica
AU - Ward, Richard
AU - Stringer, Keith
AU - Caldwell, Charles
AU - Chougnet, Claire
AU - Bezerra, Jorge A.
N1 - Funding Information:
Supported by NIH Grant DK64008 (to J. A. B.), and by the Integrative Morphology Core of the Digestive Disease Research Development Center (DK064403).
PY - 2007/6
Y1 - 2007/6
N2 - 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-γ 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-γ 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 naïve, 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.
AB - 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-γ 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-γ 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 naïve, 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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U2 - 10.1053/j.gastro.2007.04.031
DO - 10.1053/j.gastro.2007.04.031
M3 - Article
C2 - 17631148
AN - SCOPUS:34447098108
SN - 0016-5085
VL - 133
SP - 268
EP - 277
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -