Th2 cells as an intermediate for the differentiation of naïve T cells into Th9 cells, associated with the Smad3/Smad4 and IRF4 pathway.

Type 9 T-helper (Th9) cells are associated with atopic and inflammatory diseases. Their increased levels and functions contribute to a number of inflammatory disorders, where they are accompanied by enhanced Th2-cell activity. However, there is currently no consensus regarding the association between Th9 and Th2 cells. Th9 cells may be induced from naïve T (Th0) cells under specific polarization conditions in vitro, a process driven by the addition of specific cytokines. In the present study, Th0 cells were cultured under Th9-polarizing conditions to promote differentiation into interleukin (IL)-4+ IL-9- or IL-4- IL-9+ T cells after 3 or 5 days in culture, respectively; the mRNA expression levels of IL-9 and IL-4 were consistent with the induced cell types. Simultaneously, the levels of interferon-regulatory factor 4 (IRF-4) and Smad3/Smad4 were significantly increased following Th9-cell polarization. It was therefore proposed that Th2 cells may be generated in the early stages of Th9-cell differentiation, and then ultimately differentiate into Th9 cells via the Smad3/Smad4 and IRF-4 activation pathway.