CD8+ T lymphocyte response against extrahepatic biliary epithelium is activated by epitopes within NSP4 in experimental biliary atresia
| Autor: | Xiaojin Zhang, David R. Brigstock, Xuyong Chen, Hongyi Zhang, Fei Peng, Jixin Yang, Shuai-yu Zheng, Jiexiong Feng |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Physiology viruses Recombinant Fusion Proteins Epitopes T-Lymphocyte Inflammation CD8-Positive T-Lymphocytes Viral Nonstructural Proteins Epitope Rotavirus Infections Interferon-gamma Mice Cd8 t lymphocyte Biliary atresia Interferon Bile Ducts Extrahepatic Biliary Atresia Pregnancy Physiology (medical) medicine Animals Biliary epithelium Glycoproteins Toxins Biological Mice Inbred BALB C Hepatology business.industry Gastroenterology Immunization Passive Rotavirus Vaccines biochemical phenomena metabolism and nutrition medicine.disease Peptide Fragments Mice Inbred C57BL Disease Models Animal Epitope mapping Immunology Female medicine.symptom business Immunologic Memory CD8 Injections Intraperitoneal medicine.drug T-Lymphocytes Cytotoxic |
| Zdroj: | American journal of physiology. Gastrointestinal and liver physiology. 307(2) |
| ISSN: | 1522-1547 |
| Popis: | Interferon (IFN)-γ-driven and CD8+ T cell-dependent inflammatory injury to extrahepatic biliary epithelium (EHBE) is likely to be involved in the development of biliary atresia (BA). We previously showed that viral protein NSP4 is the pathogenic immunogen that causes biliary injury in BA. In this study, NSP4 or four synthetic NSP4 (NSP4157–170, NSP4144–152, NSP493–110, NSP424–32) identified by computer analysis as candidate CD8+ T cell epitopes were injected into neonatal mice. The pathogenic NSP4 epitopes were confirmed by studying extrahepatic bile duct injury, IFN-γ release and CD8+ T cell response against EHBE. The results revealed, at 7 days postinjection, inoculation of glutathione S-transferase (GST)-NSP4 caused EHBE injury and BA in neonatal mice. At 7 or 14 days postinject, inoculation of GST-NSP4, NSP4144–152, or NSP4157–170 increased IFN-γ release by CD8+ T cells, elevated the population of hepatic memory CD8+ T cells, and augmented cytotoxicity of CD8+ T cells to rhesus rotavirus (RRV)-infected or naive EHBE cells. Furthermore, depletion of CD8+ T cells in mice abrogated the elevation of GST-NSP4-induced serum IFN-γ. Lastly, parenteral immunization of mouse dams with GST-NSP4, NSP4144–152, or NSP4157–170 decreased the incidence of RRV-induced BA in their offspring. Overall, this study reports the CD8+ T cell response against EHBE is activated by epitopes within rotavirus NSP4 in experimental BA. Neonatal passive immunization by maternal vaccination against NSP4144–152 or NSP4157–170 is effective in protecting neonates from developing RRV-related BA. |
| Databáze: | OpenAIRE |
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