Recently, a research team led by Dr. CHANG Xing from the Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences, discovered that a lncRNA derived from the Il4 locus, IL4_nc, could enhance 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 secretes. IL4, IL5, IL9 and IL13 are specifically expressed in Th2 but not in other T cell subsets.

Th2 cells also express 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 were bimodally expressed in Th2 cells.

Moreover, alternative promoters are widely used in individual Th2 cells. Taking 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 indicated that IL4_nc was highly expressed in resting Th2 cells and was 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 demonstrated that cytokine genes were the major source of transcriptome heterogeneity of Th2 cells, and discovered a lncRNA, IL4_nc,  which could promote the expression of IL4.   

Published in Journal of Biological Chemistry, 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. 

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