NDLI: Transmembrane TNF- promotes suppressive activities of myeloid-derived suppressor cells via TNFR2.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Qin, Zhihai Wan, Lin Lin, Guohong Wang, Jing Yu, Min Zhao, Xianxian Yin, Bingjiao Feng, Wei Li, Baihua Jiang, Xiaodan Hu, Xin Li, Xiaoyan Li, Zhuoya
Description	Author Affiliation: Hu X ( Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.)
Abstract	It has been reported that TNFR2 is involved in regulatory T cell induction and myeloid-derived suppressor cell (MDSC) accumulation, two kinds of immunosuppressive cells contributing to tumor immune evasion. Because transmembrane TNF- (tmTNF- ) is the primary ligand for TNFR2, we hypothesized that tmTNF- is mainly responsible for the activation of MDSCs. Indeed, we found that tmTNF- , rather than secretory TNF- (sTNF- ), activated MDSCs with enhanced suppressive activities, including upregulating arginase-1 and inducible NO synthase transcription, promoting secretion of NO, reactive oxygen species, IL-10, and TGF-ß, and enhancing inhibition of lymphocyte proliferation. This effect of tmTNF- was mediated by TNFR2, as TNFR2 deficiency significantly impaired tmTNF- -induced release of IL-10 and NO and inhibition of T cell proliferation by MDSC supernatant. Furthermore, tmTNF- caused p38 phosphorylation and NF-κB activation, whereas inhibition of NF-κB or p38 with an inhibitor pyrrolidine dithiocarbamate or SB203580 abrogated tmTNF- -mediated increased suppression of lymphocyte proliferation by MDSCs. Consistently, our in vivo study showed that ectopic expression of uncleavable tmTNF- mutant by 4T1 cells significantly promoted tumor progression and angiogenesis, accompanied with more accumulation of MDSCs and regulatory T cells in the tumor site, increased production of NO, IL-10, and TGF-ß, as well as poor lymphocyte infiltration. In contrast, enforced expression of sTNF- mutant by 4T1 cells that only released sTNF- without expression of surface tmTNF- markedly reduced MDSC accumulation and induced more lymphocyte infiltration instead, showing obvious tumor regression. Our data suggest that tmTNF- acts as a potent activator of MDSCs via TNFR2 and reveals another novel immunosuppressive effect of this membrane molecule that promotes tumor immune escape.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	3
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-02-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Mammary Neoplasms, Experimental Immunology Myeloid Cells Receptors, Tumor Necrosis Factor, Type Ii Physiology Tumor Necrosis Factor-alpha Animals Arginase Biosynthesis Genetics Enzyme Induction Gene Expression Regulation, Neoplastic Lymphocyte Activation Lymphocytes, Tumor-infiltrating Map Kinase Signaling System Mice Mice, Inbred Balb C Mice, Knockout Molecular Sequence Data Nf-kappa B Metabolism Neoplasm Proteins Nitric Oxide Nitric Oxide Synthase Type Ii Reactive Oxygen Species Receptors, Tumor Necrosis Factor, Type I Deficiency Recombinant Fusion Proteins Pharmacology Solubility Specific Pathogen-free Organisms Spleen Pathology T-lymphocyte Subsets T-lymphocytes, Regulatory Up-regulation Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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