CD4 derived double negative T cells prevent the development and progression of nonalcoholic steatohepatitis

Guangyong Sun, Xinyan Zhao, Mingyang Li, Chunpan Zhang, Hua Jin, Changying Li, Liwei Liu, Yaning Wang, Wen Shi, Dan Tian, Hufeng Xu, Yue Tian, Yongle Wu, Kai Liu, Zhongtao Zhang () and Dong Zhang ()
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Guangyong Sun: Capital Medical University
Xinyan Zhao: National Clinical Research Center for Digestive Diseases
Mingyang Li: Capital Medical University
Chunpan Zhang: Capital Medical University
Hua Jin: Capital Medical University
Changying Li: Capital Medical University
Liwei Liu: National Clinical Research Center for Digestive Diseases
Yaning Wang: Capital Medical University
Wen Shi: Capital Medical University
Dan Tian: Capital Medical University
Hufeng Xu: Capital Medical University
Yue Tian: Capital Medical University
Yongle Wu: Capital Medical University
Kai Liu: Capital Medical University
Zhongtao Zhang: Capital Medical University
Dong Zhang: Capital Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20941-x

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