miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg).

Abstract

Thymic-derived regulatory T cell (tTreg) clinical trials show therapeutic promise in the prevention of acute graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation patients. However, strategies are needed to improve tTreg proliferative ability and survival as a means to improve tTreg therapy and reduce the requirement for producing large numbers of Treg cells for adoptive tTreg transfer. Autophagy is a self-degradative process for cytosolic components, which is involved in cells death, differentiation, lymphocyte homeostasis, and tTreg function. Studies have shown that mice with tTreg cells that have a disrupted autophagy process have defective tTreg cell generation and function, resulting in autoimmune disease and failed GVHD prevention by adoptively transferred tTreg cells. We found the attenuated autophagy status during ex vivo expansion, which leads us to determine whether tTreg cell survival could be augmented by miR-142-3p, the miRNA which is highly expressed in tTreg cells and potentially targets autophagy-related protein (ATG)-1, ATG16L1. We demonstrate that miR-142-3p downregulates ATG16L1 mRNA and production of ATG16L1, that has been linked to autoimmune diseases. Conversely, miR-142-3p knock-down improved tTreg cell expansion, survival and function in vitro and vivo. In aggregate, these studies provide a new approach that uses miR-142-3p knockdown to increase tTreg cell efficacy by increasing ATG16L1 mRNA and protein and the autophagy process.

• Authors: Yunjie Lu, Ji Gao, Shaopeng Zhang, Jian Gu, Hao Lu, Yongxiang Xia, Qin Zhu, Xiaofeng Qian, Feng Zhang, Chuanyong Zhang, Hongbing Shen, Keli L Hippen, Bruce R Blazar, Ling Lu, Xuehao Wang
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 3 Pg. 290 (02 19 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29459719 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Atg16l1 protein, mouse
• Autophagy-Related Proteins
• Carrier Proteins
• MicroRNAs
• Mirn142 microRNA, mouse

Topics

• Animals
• Autophagy
• Autophagy-Related Proteins
• Carrier Proteins (genetics, immunology)
• Cell Differentiation
• Cell Proliferation
• Cells, Cultured
• Humans
• Mice
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• MicroRNAs (genetics, immunology, metabolism)
• T-Lymphocytes, Regulatory (cytology, immunology)
• Thymus Gland (cytology, immunology)