Dendritic cell Piezo1 directs the differentiation of TH1 and Treg cells in cancer
Yuexin Wang,
Hui Yang,
Anna Jia,
Yufei Wang,
Qiuli Yang,
Yingjie Dong,
Yueru Hou,
Yejin Cao,
Lin Dong,
Yujing Bi,
Guangwei Liu
Affiliations
Yuexin Wang
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Hui Yang
Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Anna Jia
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Yufei Wang
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Qiuli Yang
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Yingjie Dong
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Yueru Hou
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Yejin Cao
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Lin Dong
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Yujing Bi
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China
Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, College of Life Sciences, Beijing Normal University, Beijing, China
Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth in mice. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGFβ1 and IL-12, leading to increased TGFβR2-p-Smad3 activity and decreased IL-12Rβ2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1α)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGFβ1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.
