Abstract

Hepatic inflammation is the driving force for the development and progression of NASH. Treatment targeting inflammation is believed to be beneficial. In this study, adoptive transfer of CD4+ T cells converted double negative T cells (cDNT) protects mice from diet-induced liver fat accumulation, lobular inflammation and focal necrosis. cDNT selectively suppress liver-infiltrating Th17 cells and proinflammatory M1 macrophages. IL-10 secreted by M2 macrophages decreases the survival and function of cDNT to protect M2 macrophages from cDNT-mediated lysis. NKG2A, a cell inhibitory molecule, contributes to IL-10 induced apoptosis and dampened suppressive function of cDNT. In conclusion, ex vivo-generated cDNT exert potent protection in diet induced obesity, type 2 diabetes and NASH. The improvement of outcome is due to the inhibition on liver inflammatory cells. This study supports the concept and the feasibility of potentially utilizing this autologous immune cell-based therapy for the treatment of NASH.

Hepatic inflammation contributes to the development of nonalcoholic steatohepatitis (NASH). Here, the authors show that a transfer of ex vivo generated CD4 derived double negative T cells can prevent the development and progression of NASH by suppression of inflammatory Th17 cells and M1 macrophages in mouse models.

Details

Title
CD4 derived double negative T cells prevent the development and progression of nonalcoholic steatohepatitis
Author
Sun, Guangyong 1 ; Zhao, Xinyan 2 ; Li, Mingyang 3 ; Zhang Chunpan 3 ; Jin, Hua 3 ; Li Changying 3 ; Liu, Liwei 2 ; Wang, Yaning 3 ; Shi, Wen 3 ; Tian, Dan 3   VIAFID ORCID Logo  ; Xu Hufeng 3 ; Tian Yue 3 ; Wu Yongle 4 ; Liu, Kai 3 ; Zhang, Zhongtao 5 ; Zhang, Dong 6   VIAFID ORCID Logo 

1  Capital Medical University, General Surgery Department, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Capital Medical University, Experimental and Translational Research Center, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Beijing Clinical Research Institute, Beijing, China (GRID:grid.24696.3f); Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China (GRID:grid.24696.3f); Capital Medical University, Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X) 
2  National Clinical Research Center for Digestive Diseases, Beijing, China (GRID:grid.24696.3f) 
3  Capital Medical University, Experimental and Translational Research Center, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Beijing Clinical Research Institute, Beijing, China (GRID:grid.24696.3f); Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China (GRID:grid.24696.3f); Capital Medical University, Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X) 
4  Capital Medical University, Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X) 
5  Capital Medical University, General Surgery Department, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China (GRID:grid.24696.3f); National Clinical Research Center for Digestive Diseases, Beijing, China (GRID:grid.24696.3f) 
6  Capital Medical University, General Surgery Department, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Capital Medical University, Experimental and Translational Research Center, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); Beijing Clinical Research Institute, Beijing, China (GRID:grid.24696.3f); Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, China (GRID:grid.24696.3f); Capital Medical University, Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Beijing, China (GRID:grid.24696.3f) (ISNI:0000 0004 0369 153X); National Clinical Research Center for Digestive Diseases, Beijing, China (GRID:grid.24696.3f) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-20941-x
ProQuest document ID
2482357763
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.