A recent study entitled “Single-cell RNA-Seq analysis identifies a noncoding interleukin 4 (IL-4) RNA that post-transcriptionally up-regulates IL-4 production in T helper cells” has been published online in Journal of Biological Chemistry on January 4^th, 2019. This work discovered that a lncRNA derived from the Il4 locus, IL4_nc, enhances translation of IL4 mRNA in Th2 cells.   

Type 2 T helper (Th2) cell is a subset of CD4+ T cells, and is a key mediator during immune response against parasites and humoral immune response, which depends on the cytokines Th2 secreted. IL4, IL5, IL9 and IL13 are specifically expressed in Th2 but not in other T cell subsets; Th2 cells also expresse universal cytokines such as IL2 and TNFα, which are commonly expressed in all T cell subsets. Even cultured in the same environment the cytokines expressed in Th2 cells vary greatly, a phenomena which is still not fully understood.    

In the study, to uncover the heterogeneity of Th2 lineage, researchers first conducted single-cell RNA sequencing using Fluidigm C1 platform. They revealed that cytokine genes were major contributors of cellular heterogeneity of in vitro differentiated Th2 cells, and universal cytokines are bimodally expressed in Th2 cells. Moreover, alternative promoters are widely used in individual Th2 cells. Taken IL4_nc as an example, IL4_nc shares the last three exons but uses a different first exon compared to the coding IL4 mRNA. Further study indicates that IL4_nc is highly expressed in resting Th2 cells and is induced by TCR re-stimulation. Knockdown and over-expression of IL4_nc in in vitro differentiated Th2 cells further demonstrated that IL4_nc promoted translation of IL4 mRNA increasing IL4 expression. 3’ sequence of IL4_nc which is the same with 3’UTR of IL4 mRNA is essential for the regulation of IL4, probably by adsorbing or segregating inhibitory factors of IL4 mRNA translation.    

This work demonstrates that cytokine genes are the major source of transcriptome heterogeneity of Th2 cells, and discovered a lncRNA, IL4_nc, promotes expression of IL4.   

This work was mostly completed by research team led by Dr. CHANG Xing from Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences. The study was supported by the National Key Research and Development Plan of China, National Natural Science Foundation of China, and Chinese Academy of Sciences, etc. 

lncRNA IL4_nc up-regulates the expression of IL4 protein in Th2 cells.
(Image by Dr CHANG Xing's Group)