Credit: PHOTOALTO

The differentiation of T helper (TH) cell subsets is controlled by unique sets of transcription factors; these regulate the expression of cytokines and other genes that are important for the effector functions of each subset. Recent reports have described an interleukin-9 (IL-9)-producing population of T cells, which is induced in vitro following culture with IL-4 and transforming growth factor-β (TGFβ). These cells are related to the TH2 cell lineage but express lower levels of TH2-type cytokines, and they have therefore been proposed to be a new subset of 'TH9' cells. However, this classification has been controversial owing to the lack of any TH9 cell-specific transcription factor (or factors). Now, Chang et al. have strengthened the case for a 'TH9 cell lineage' by identifying PU.1 as a transcription factor that uniquely promotes the TH9 cell phenotype.

Previous studies showed that PU.1 can suppress the production of TH2-type cytokines, prompting the authors to examine the role of this transcription factor in the induction of TH9 cells. Following culture under TH9 cell-promoting conditions, PU.1-deficient T cells produced substantially lower levels of IL-9, suggesting that PU.1 was important for TH9 cell development. In further support of this, there were higher levels of PU.1-encoding mRNA in TH9 cells than in TH1, TH2 or TH17 cells. PU.1 was required for chromatin modifications at the Il9 locus, with chromatin immunoprecipitation and DNA-affinity precipitation assays showing direct binding of PU.1 to conserved non-coding sequences in the Il9 promoter. Importantly, the authors found human TH9 cells can also be induced in vitro in response to culture with IL-4 and TGFβ, and PU.1 was also necessary for human TH9 cell differentiation.

Next, the authors investigated the function of TH9 cells in vivo, examining their roles in allergic responses. In a model of allergic airway inflammation, mice with a T cell-specific deficiency in PU.1 showed lower levels of lung inflammation than wild-type mice. This was characterized by fewer inflammatory infiltrates and decreased airway hyperresponsiveness and seemed to be due to the specific absence of TH9 cells, as both TH2 and TH17 cells developed normally in these animals. Treating wild-type mice with IL-9-specific blocking antibodies during the induction of airway inflammation led to a similar decrease in inflammation, suggesting that IL-9 itself was important for promoting the inflammatory response in the lung.

The identification of PU.1 as a specific transcription factor for TH9 cells suggests that these cells may be a bona fide TH cell lineage. Furthermore, these data suggest that targeting IL-9 could be a useful therapy for treating patients with asthma and other allergies.