ABSTRACT
N6-methyladenosine (m6A) methyltransferase Mettl3 is involved in conventional T cell immunity; however, its role in innate immune cells remains largely unknown. Here, we show that Mettl3 intrinsically regulates invariant natural killer T (iNKT) cell development and function in an m6A-dependent manner. Conditional ablation of Mettl3 in CD4+CD8+ double-positive (DP) thymocytes impairs iNKT cell proliferation, differentiation, and cytokine secretion, which synergistically causes defects in B16F10 melanoma resistance. Transcriptomic and epi-transcriptomic analyses reveal that Mettl3 deficiency disturbs the expression of iNKT cell-related genes with altered m6A modification. Strikingly, Mettl3 modulates the stability of the Creb1 transcript, which in turn controls the protein and phosphorylation levels of Creb1. Furthermore, conditional targeting of Creb1 in DP thymocytes results in similar phenotypes of iNKT cells lacking Mettl3. Importantly, ectopic expression of Creb1 largely rectifies such developmental defects in Mettl3-deficient iNKT cells. These findings reveal that the Mettl3-m6A-Creb1 axis plays critical roles in regulating iNKT cells at the post-transcriptional layer.
Subject(s)
Cell Differentiation , Natural Killer T-Cells , Cell Differentiation/genetics , Methyltransferases , Proteins , Thymocytes , Animals , MiceABSTRACT
The chemical industry poses a potential security risk to factory personnel and neighboring residents. In order to mitigate prospective damage, a synthetic method must be developed for an emergency response. With the development of environmental numeric simulation models, model integration methods, and modern information technology, many Decision Support Systems (DSSs) have been established. However, existing systems still have limitations, in terms of synthetic simulation and network interoperation. In order to resolve these limitations, the matured simulation model for chemical accidents was integrated into the WEB Geographic Information System (WEBGIS) platform. The complete workflow of the emergency response, including raw data (meteorology information, and accident information) management, numeric simulation of different kinds of accidents, environmental impact assessments, and representation of the simulation results were achieved. This allowed comprehensive and real-time simulation of acute accidents in the chemical industry. The main contribution of this paper is that an organizational mechanism of the model set, based on the accident type and pollutant substance; a scheduling mechanism for the parallel processing of multi-accident-type, multi-accident-substance, and multi-simulation-model; and finally a presentation method for scalar and vector data on the web browser on the integration of a WEB Geographic Information System (WEBGIS) platform. The outcomes demonstrated that this method could provide effective support for deciding emergency responses of acute chemical accidents.
