Smad1 Deficiency Affects Th9 Cell Differentiation

T helper cell 9 that is different from Thl and Th2 cells,is a subset of T cell that secrete IL-9,IL-10 and IL-21 cytokines.Th9 cells exert their effects mainly through the secretion of IL-9,and are also involved in the pathogenesis of allergic asthma,tuberculosis,experimental autoimmune encephalomyelitis,rheumatoid arthritis,Tumor and other disease processes.In vitro,the combination of IL-4 and TGF-β can promote the differentiation of naive T cells into Th9 cells.In Th9 cells,TGF-(3-activated Smad3 signaling pathway is required for 119 gene expression,which also indicates that TGF-(3 contributes to Th9 differentiation and development.Smad1,Smad2,Smad3 and Smad5 are members of the SMADs family that interact and are phosphorylated by specific type I threonine kinase receptors and then activate the downstream signaling pathways.It is reported that TGF-P and BMP-2 or BMP-4 can also activate Smadl signaling pathway,promote the phosphorylation of Smadl protein,then translocating into the nucleus to promote the transcriptional expression of related target genes.Therefore,TGF-P activates Smad3 signaling pathway and activates Smadl signaling pathway.The role of Smadl in Th9 cell differentiation and development remains unclear.We knocked down the Smad1 gene in CD4+ T cells by using CD4CreSmad1fl/fl mice and then induced the differentiation of Th9 cells to explore the role of Smadl in the differentiation and development of Th9 cells and related mechanisms.We found that CD4CreSmad1fl/fl mice lacked Smadl gene,but development and activation of T cell from thymus and peripheral lymph organ were not affected.The results of flow cytometry showed that Smadl deficiency had no significant effect on the differentiation of Th1,Th2,Th17 and Treg cells,but promoted the differentiation of Th9 cells with the increased levels of IL-9 and enhanced mRNA expression of IL-9.The type I BMP receptor kinase inhibitor LDN193189 blocked the Smadl signaling pathway and enhances the differentiation of Th9 cells.On the contrary,using BMP4 to activate Smadl signaling pathway,the differentiation of Th9 cells was inhibited and the protein level of PU.1 transcription factor was down-regulated.TGF-β promoted the translocation of Smad3 into the nucleus and promoted Th9 cell differentiation.Therefore,we hypothesize that Smadl deficiency promotes Smad3 phosphorylation under Th9 cell-induced conditions,and promotes its translocation into nucleus,and promotes the transcriptional expression of PU.1,thereby promoting Th9 cell differentiation.In summary,by examining whether Smadl can affect Th9 cell differentiation,we can gain insights into the mechanisms involved in Th9 cell differentiation and are intended to provide nw ideas and targets for the treatment of Th9-related allergic respiratory inflammation,autoimmune diseases,skin inflammation and tumor.