Th9 cells: differentiation and disease

Abstract

CD4(+) T-helper cells regulate immunity and inflammation through the acquisition of potential to secrete specific cytokines. The acquisition of cytokine-secreting potential, in a process termed T-helper cell differentiation, is a response to multiple environmental signals including the cytokine milieu. The most recently defined subset of T-helper cells are termed Th9 and are identified by the potent production of interleukin-9 (IL-9). Given the pleiotropic functions of IL-9, Th9 cells might be involved in pathogen immunity and immune-mediated disease. In this review, I focus on recent developments in understanding the signals that promote Th9 differentiation, the transcription factors that regulate IL-9 expression, and finally the potential roles for Th9 cells in immunity in vivo.

Fig. 1. Regulation of Il9 in Th9 cells

Schematic of the Il9 gene indicating the intron–exon structure and the transcriptional start site from the anti-sense strand, with numbering on mouse chromosome 13 according to GRCm38. Conserved non-coding sequences (CNS) are indicated by red bars, CNS0 is −6.3 kb from the transcriptional start site (TSS), CNS1 is the Il9 promoter, and CNS2 is +5kb from the TSS (1, 35). The lower schematic indicates the 300 bp, numbered from the TSS, in CNS1. In our previous work, we performed bioinformatics analysis of these sequences; in contrast, this schematic focuses on experimentally determined binding sites for transcription factors that regulate Il9 expression. NF-κB and NFAT sites (−46; −313) were identified by Jash et al. and Xiao et al. (33, 36). PU.1-binding sites (−194; −309) were determined by Chang et al. (1). Smad and RBP-Jκ sites (−4065 and −4270, respectively) were defined by Elyaman et al. (14). IRF4 binding and regulation was determined by Staudt et al., and potential binding sites (−100; −240, sense strand orientation) were defined by Perumal and Kaplan (3, 35).

Fig. 2. Functions of Th9 cells

Although the functions of Th9 cells have not been completely documented, they have been shown to have roles in several types of inflammatory disease. The diagram indicates the ability of Th9 cells to regulate allergic inflammation, autoimmune inflammation, and anti-tumor immunity, and documents some of the features of Th9-mediated function in each inflammatory scenario.