Dendritic cell Piezo1 directs the differentiation of T<sub>H</sub>1 and T<sub>reg</sub> cells in cancer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35993548.
- Also identified by DOI 10.7554/eLife.79957 and PMC identifier 9451538.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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 T<sub>H</sub>1 and regulatory T (T<sub>reg</sub>) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of T<sub>H</sub>1 cells while driving the development of T<sub>reg</sub> 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 T<sub>reg</sub> and T<sub>H</sub>1 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 T<sub>H</sub>1 and T<sub>reg</sub> 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.
Medical subject headings
- Ion Channels
- Neoplasms
- Th1 Cells