Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA
Background and Aims: Biliary atresia (BA) entails an inflammatory injury of the biliary tree, leading to fibrosis of the extrahepatic and intrahepatic bile ducts. The chronic inflammatory biliary injury may be due to lack of appropriate regulatory T cell (Treg) suppression of inflammation. The aims...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Gastro Hep Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772572322000097 |
| _version_ | 1818530070205038592 |
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| author | Yuhuan Luo Joseph Bednarek Alexander Chaidez Shaikh Atif Dong Wang Cara L. Mack |
| author_facet | Yuhuan Luo Joseph Bednarek Alexander Chaidez Shaikh Atif Dong Wang Cara L. Mack |
| author_sort | Yuhuan Luo |
| collection | DOAJ |
| description | Background and Aims: Biliary atresia (BA) entails an inflammatory injury of the biliary tree, leading to fibrosis of the extrahepatic and intrahepatic bile ducts. The chronic inflammatory biliary injury may be due to lack of appropriate regulatory T cell (Treg) suppression of inflammation. The aims of the study were to characterize Treg deficits in human BA and to determine if Treg augmentation therapy improved outcomes in the rhesus rotavirus (RRV)–induced mouse model of BA. Methods: Immunophenotyping of human peripheral blood and liver Tregs was performed with flow cytometry, Vectra-6 multicolor immunohistochemistry (IHC), and real-time polymerase chain reaction. Measured outcomes of Treg augmentation with the interleukin-2 monoclonal antibody JES6-1/interleukin-2 in the RRV-induced mouse model of BA included survival, direct bilirubin, IHC, and liver flow cytometry. Results: Patients with BA had decreased peripheral blood Treg frequency and lack of cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) upregulation despite a highly activated, effector Treg phenotype. IHC revealed decreased liver Treg frequency and Treg CTLA-4 expression. Treg augmentation in the murine model led to increased survival, decreased direct bilirubin levels and liver inflammation, and expansion of resident macrophages. In addition to the M2 phenotype of resident macrophages, these cells adopted an inflammatory M1 phenotype in response to RRV infection, which was inhibited with Treg augmentation. Conclusion: Patients with BA have Treg deficiencies associated with lack of sufficient CTLA-4 expression that is necessary for cell-cell contact inhibition of inflammatory responses. Treg augmentation therapy in murine BA protected from disease. Future treatment trials for BA should include agents that enhance Treg number or function, mimic CTLA-4 function, and promote anti-inflammatory M2 macrophage phenotypes. |
| first_indexed | 2024-12-11T17:15:05Z |
| format | Article |
| id | doaj.art-06eaf4ff4f404e33a4639589faf7a709 |
| institution | Directory Open Access Journal |
| issn | 2772-5723 |
| language | English |
| last_indexed | 2024-12-11T17:15:05Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Gastro Hep Advances |
| spelling | doaj.art-06eaf4ff4f404e33a4639589faf7a7092022-12-22T00:57:21ZengElsevierGastro Hep Advances2772-57232022-01-0113461470Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BAYuhuan Luo0Joseph Bednarek1Alexander Chaidez2Shaikh Atif3Dong Wang4Cara L. Mack5Section of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine. Aurora, ColoradoDepartment of Pathology, University of Utah. Salt Lake City, UtahSection of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine. Aurora, ColoradoDivision of Allergy & Immunology, Department of Medicine, University of Colorado School of Medicine. Aurora, ColoradoUniversity of Colorado School of Medicine. Aurora, ColoradoSection of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine. Aurora, Colorado; Correspondence: Address correspondence to: Cara L. Mack, MD, Professor of Pediatrics, Section of Gastroenterology, Hepatology & Nutrition, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado School of Medicine, 13123 E 16th Ave., B290, Aurora, Clorado 80111.Background and Aims: Biliary atresia (BA) entails an inflammatory injury of the biliary tree, leading to fibrosis of the extrahepatic and intrahepatic bile ducts. The chronic inflammatory biliary injury may be due to lack of appropriate regulatory T cell (Treg) suppression of inflammation. The aims of the study were to characterize Treg deficits in human BA and to determine if Treg augmentation therapy improved outcomes in the rhesus rotavirus (RRV)–induced mouse model of BA. Methods: Immunophenotyping of human peripheral blood and liver Tregs was performed with flow cytometry, Vectra-6 multicolor immunohistochemistry (IHC), and real-time polymerase chain reaction. Measured outcomes of Treg augmentation with the interleukin-2 monoclonal antibody JES6-1/interleukin-2 in the RRV-induced mouse model of BA included survival, direct bilirubin, IHC, and liver flow cytometry. Results: Patients with BA had decreased peripheral blood Treg frequency and lack of cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) upregulation despite a highly activated, effector Treg phenotype. IHC revealed decreased liver Treg frequency and Treg CTLA-4 expression. Treg augmentation in the murine model led to increased survival, decreased direct bilirubin levels and liver inflammation, and expansion of resident macrophages. In addition to the M2 phenotype of resident macrophages, these cells adopted an inflammatory M1 phenotype in response to RRV infection, which was inhibited with Treg augmentation. Conclusion: Patients with BA have Treg deficiencies associated with lack of sufficient CTLA-4 expression that is necessary for cell-cell contact inhibition of inflammatory responses. Treg augmentation therapy in murine BA protected from disease. Future treatment trials for BA should include agents that enhance Treg number or function, mimic CTLA-4 function, and promote anti-inflammatory M2 macrophage phenotypes.http://www.sciencedirect.com/science/article/pii/S2772572322000097Bile DuctChildrenCholestasisCytotoxic T Lymphocyte–associated Antigen-4Forkhead Box P3 |
| spellingShingle | Yuhuan Luo Joseph Bednarek Alexander Chaidez Shaikh Atif Dong Wang Cara L. Mack Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA Gastro Hep Advances Bile Duct Children Cholestasis Cytotoxic T Lymphocyte–associated Antigen-4 Forkhead Box P3 |
| title | Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA |
| title_full | Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA |
| title_fullStr | Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA |
| title_full_unstemmed | Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA |
| title_short | Regulatory T Cell (Treg) Cytotoxic T Lymphocyte–associated Antigen-4 Deficits in Biliary Atresia (BA) and Disease Rescue With Treg Augmentation in Murine BA |
| title_sort | regulatory t cell treg cytotoxic t lymphocyte associated antigen 4 deficits in biliary atresia ba and disease rescue with treg augmentation in murine ba |
| topic | Bile Duct Children Cholestasis Cytotoxic T Lymphocyte–associated Antigen-4 Forkhead Box P3 |
| url | http://www.sciencedirect.com/science/article/pii/S2772572322000097 |
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